Progress and challenges in RET-targeted cancer therapy

doi:10.1007/s11684-023-0985-y

Front. Med.

2023, Vol. 17

Issue (2) : 207-219 https://doi.org/10.1007/s11684-023-0985-y

REVIEW

Progress and challenges in RET-targeted cancer therapy

Xueqing Hu, Ujjwol Khatri, Tao Shen, Jie Wu(

)

Peggy and Charles Stephenson Cancer Center, and Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA

Download: PDF(2434 KB) HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Abstract

The rearranged during transfection (RET) is a receptor protein tyrosine kinase. Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer (NSCLC) and in thyroid cancer, but also increasingly in various types of cancers at low rates. In the last few years, two potent and selective RET protein tyrosine kinase inhibitors (TKIs), pralsetinib (BLU-667) and selpercatinib (LOXO-292, LY3527723) were developed and received regulatory approval. Although pralsetinib and selpercatinib gave high overall response rates (ORRs), < 10% of patients achieved a complete response (CR). The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations, acquired alternative oncogenes, or MET amplification. RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib. Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials. However, it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs. Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.

Keywords pralsetinib selpercatinib RET-alteration lung cancer thyroid cancer tumor-agnostic therapy drug resistance

Corresponding Author(s): Jie Wu

Just Accepted Date: 29 March 2023 Online First Date: 26 April 2023 Issue Date: 26 May 2023

Cite this article:

Xueqing Hu,Ujjwol Khatri,Tao Shen, et al. Progress and challenges in RET-targeted cancer therapy[J]. Front. Med., 2023, 17(2): 207-219.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-0985-y
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I2/207

Fig.1 RET and oncogenic RET mutations. (A) Schematic presentation of RET protein domains and the locations of oncogenic RET mutations. The different C-terminal regions of RET51 and RET9 are shown. Listed mutations are the likely pathogenic and pathogenic RET variants annotated by ARUP Laboratories, and additional indels reported in thyroid cancer patients in a clinical study (in italic) [20]. (B) RET-GFRα1/GDNF complex structure (PDB id: 6Q2N), CRD-TM region, kinase domain (PDB id: 6NJA), major tyrosine phosphorylation sites and major signaling pathways. Left, top view of RET-GFRα1/GDNF complex structure. Right, side view of the RET extracellular domain structure, CRD-TM region, and intracellular region. The co-receptor and the ligand are removed for clarity. The amino acid residues of the linker region between the CRD-TM domain are shown (not drawn to the scale). The potential natural and unnatural disulfide bridges are indicated. PM, plasma membrane.

Fig.2 Common RET fusions. Schematic presentation of the three most common RET fusion oncoprotein kinases drawn to scale. Multiple KIF5B-RET fusions have been detected in cancer patients that differ in the KIF5B and RET breakpoints. Only the most common form of KIF5B-RET (K15;R12) is shown. PTK, protein tyrosine kinase domain. CC, coiled-coil domain. KISc, kinesin motor domain.

Tab.1 Comparison of ESMO recommended technologies to detect RET alterations in clinical research and practice

Fig.3 Regulatory approved RET-targeting TKIs (pralsetinib and selpercatinib) and new RET TKIs in clinical development. (A) Chemical structures of pralsetinib, selpercatinib, TPX-0046, and BOS172738. Chemical structures of other TKIs listed in B have not been publicly disclosed. (B) Sensitivities of approved and new clinical stage RET TKIs toward RET kinase domain variants and other protein tyrosine kinases.

Tab.2 Efficacies of selpercatinib and pralsetinib in clinical trials

Fig.4 Schematic diagram of tumor evolution to acquired resistance to pralsetinib and selpercatinib. > 90% of patients treated with pralsetinib or selpercatinib have radioimaging-detectable residual tumors. During the transition state, the TKI maintains the residual tumors at small sizes while the drug-tolerated persisters adapt to the drug pressure by slightly adjusting signaling pathways, remodeling epigenome, and accumulating genetic mutations. At some points, an acquired genetic event allows the tumor to overcome the drug pressure for rapid tumor growth, resulting in the acquired resistance.

Tab.3 Next-generation of RET TKIs in clinical studies

1	LM Mulligan. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer 2014; 14(3): 173–186 https://doi.org/10.1038/nrc3680 pmid: 24561444
2	KZ Thein, V Velcheti, BHM Mooers, J Wu, V Subbiah. Precision therapy for RET-altered cancers with RET inhibitors. Trends Cancer 2021; 7(12): 1074–1088 https://doi.org/10.1016/j.trecan.2021.07.003 pmid: 34391699
3	A Drilon, ZI Hu, GGY Lai, DSW Tan. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol 2018; 15(3): 151–167 https://doi.org/10.1038/nrclinonc.2017.175 pmid: 29134959
4	X Liu, X Hu, T Shen, Q Li, BHM Mooers, J Wu. RET kinase alterations in targeted cancer therapy. Cancer Drug Resist 2020; 3(3): 472–481 https://doi.org/10.20517/cdr.2020.15 pmid: 35582449
5	V Subbiah, D Yang, V Velcheti, A Drilon, F Meric-Bernstam. State-of-the-art strategies for targeting RET-dependent cancers. J Clin Oncol 2020; 38(11): 1209–1221 https://doi.org/10.1200/JCO.19.02551 pmid: 32083997
6	Z Piotrowska, H Isozaki, JK Lennerz, JF Gainor, IT Lennes, VW Zhu, N Marcoux, MK Banwait, SR Digumarthy, W Su, S Yoda, AK Riley, V Nangia, JJ Lin, RJ Nagy, RB Lanman, D Dias-Santagata, M Mino-Kenudson, AJ Iafrate, RS Heist, AT Shaw, EK Evans, C Clifford, SI Ou, B Wolf, AN Hata, LV Sequist. Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion. Cancer Discov 2018; 8(12): 1529–1539 https://doi.org/10.1158/2159-8290.CD-18-1022 pmid: 30257958
7	Z Zhao, C Su, W Xiu, W Wang, S Zeng, M Huang, Y Gong, Y Lu, Y Zhang. Response to pralsetinib observed in meningeal-metastatic EGFR-mutant NSCLC with acquired RET fusion: a brief report. JTO Clin Res Rep 2022; 3(6): 100343 https://doi.org/10.1016/j.jtocrr.2022.100343 pmid: 35711719
8	C Wang, Z Zhang, Y Sun, S Wang, M Wu, Q Ou, Y Xu, Z Chen, Y Shao, H Liu, P Hou. RET fusions as primary oncogenic drivers and secondary acquired resistance to EGFR tyrosine kinase inhibitors in patients with non-small-cell lung cancer. J Transl Med 2022; 20(1): 390 https://doi.org/10.1186/s12967-022-03593-3 pmid: 36059009
9	MM Awad, S Liu, II Rybkin, KC Arbour, J Dilly, VW Zhu, ML Johnson, RS Heist, T Patil, GJ Riely, JO Jacobson, X Yang, NS Persky, DE Root, KE Lowder, H Feng, SS Zhang, KM Haigis, YP Hung, LM Sholl, BM Wolpin, J Wiese, J Christiansen, J Lee, AB Schrock, LP Lim, K Garg, M Li, LD Engstrom, L Waters, JD Lawson, P Olson, P Lito, SI Ou, JG Christensen, PA Jänne, AJ Aguirre. Acquired resistance to KRASG12C inhibition in cancer. N Engl J Med 2021; 384(25): 2382–2393 https://doi.org/10.1056/NEJMoa2105281 pmid: 34161704
10	JJ Adashek, AP Desai, AY Andreev-Drakhlin, J Roszik, GJ Cote, V Subbiah. Hallmarks of RET and co-occuring genomic alterations in RET-aberrant cancers. Mol Cancer Ther 2021; 20(10): 1769–1776 https://doi.org/10.1158/1535-7163.MCT-21-0329 pmid: 34493590
11	A Hegde, AY Andreev-Drakhlin, J Roszik, L Huang, S Liu, K Hess, M Cabanillas, MI Hu, NL Busaidy, SI Sherman, R Dadu, EG Grubbs, SM Ali, J Lee, YY Elamin, GR Simon, GR Jr Blumenschein, VA Papadimitrakopoulou, D Hong, F Meric-Bernstam, J Heymach, V Subbiah. Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies. ESMO Open 2020; 5(5): e000799 https://doi.org/10.1136/esmoopen-2020-000799 pmid: 33097651
12	M Saito, K Shiraishi, H Kunitoh, S Takenoshita, J Yokota, T Kohno. Gene aberrations for precision medicine against lung adenocarcinoma. Cancer Sci 2016; 107(6): 713–720 https://doi.org/10.1111/cas.12941 pmid: 27027665
13	J Mazieres, A Drilon, A Lusque, L Mhanna, AB Cortot, L Mezquita, AA Thai, C Mascaux, S Couraud, R Veillon, den Heuvel M Van, J Neal, N Peled, M Früh, TL Ng, V Gounant, S Popat, J Diebold, J Sabari, VW Zhu, SI Rothschild, P Bironzo, A Martinez-Marti, A Curioni-Fontecedro, R Rosell, M Lattuca-Truc, M Wiesweg, B Besse, B Solomon, F Barlesi, RD Schouten, H Wakelee, DR Camidge, G Zalcman, S Novello, SI Ou, J Milia, O Gautschi. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019; 30(8): 1321–1328 https://doi.org/10.1093/annonc/mdz167 pmid: 31125062
14	O Gautschi, J Milia, T Filleron, J Wolf, DP Carbone, D Owen, R Camidge, V Narayanan, RC Doebele, B Besse, J Remon-Masip, PA Janne, MM Awad, N Peled, CC Byoung, DD Karp, Den Heuvel M Van, HA Wakelee, JW Neal, TSK Mok, JCH Yang, SI Ou, G Pall, P Froesch, G Zalcman, DR Gandara, JW Riess, V Velcheti, K Zeidler, J Diebold, M Früh, S Michels, I Monnet, S Popat, R Rosell, N Karachaliou, SI Rothschild, JY Shih, A Warth, T Muley, F Cabillic, J Mazières, A Drilon. Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry. J Clin Oncol 2017; 35(13): 1403–1410 https://doi.org/10.1200/JCO.2016.70.9352 pmid: 28447912
15	V Subbiah, JF Gainor, R Rahal, JD Brubaker, JL Kim, M Maynard, W Hu, Q Cao, MP Sheets, D Wilson, KJ Wilson, L DiPietro, P Fleming, M Palmer, MI Hu, L Wirth, MS Brose, SI Ou, M Taylor, E Garralda, S Miller, B Wolf, C Lengauer, T Guzi, EK Evans. Precision targeted therapy with BLU-667 for RET-driven cancers. Cancer Discov 2018; 8(7): 836–849 https://doi.org/10.1158/2159-8290.CD-18-0338 pmid: 29657135
16	V Subbiah, V Velcheti, BB Tuch, K Ebata, NL Busaidy, ME Cabanillas, LJ Wirth, S Stock, S Smith, V Lauriault, S Corsi-Travali, D Henry, M Burkard, R Hamor, K Bouhana, S Winski, RD Wallace, D Hartley, S Rhodes, M Reddy, BJ Brandhuber, S Andrews, SM Rothenberg, A Drilon. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol 2018; 29(8): 1869–1876 https://doi.org/10.1093/annonc/mdy137 pmid: 29912274
17	JF Gainor, G Curigliano, DW Kim, DH Lee, B Besse, CS Baik, RC Doebele, PA Cassier, G Lopes, DSW Tan, E Garralda, LG Paz-Ares, BC Cho, SM Gadgeel, M Thomas, SV Liu, MH Taylor, AS Mansfield, VW Zhu, C Clifford, H Zhang, M Palmer, J Green, CD Turner, V Subbiah. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol 2021; 22(7): 959–969 https://doi.org/10.1016/S1470-2045(21)00247-3 pmid: 34118197
18	A Drilon, GR Oxnard, DSW Tan, HHF Loong, M Johnson, J Gainor, CE McCoach, O Gautschi, B Besse, BC Cho, N Peled, J Weiss, YJ Kim, Y Ohe, M Nishio, K Park, J Patel, T Seto, T Sakamoto, E Rosen, MH Shah, F Barlesi, PA Cassier, L Bazhenova, F De Braud, E Garralda, V Velcheti, M Satouchi, K Ohashi, NA Pennell, KL Reckamp, GK Dy, J Wolf, B Solomon, G Falchook, K Ebata, M Nguyen, B Nair, EY Zhu, L Yang, X Huang, E Olek, SM Rothenberg, K Goto, V Subbiah. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med 2020; 383(9): 813–824 https://doi.org/10.1056/NEJMoa2005653 pmid: 32846060
19	V Subbiah, MI Hu, LJ Wirth, M Schuler, AS Mansfield, G Curigliano, MS Brose, VW Zhu, S Leboulleux, DW Bowles, CS Baik, D Adkins, B Keam, I Matos, E Garralda, JF Gainor, G Lopes, CC Lin, Y Godbert, D Sarker, SG Miller, C Clifford, H Zhang, CD Turner, MH Taylor. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol 2021; 9(8): 491–501 https://doi.org/10.1016/S2213-8587(21)00120-0 pmid: 34118198
20	LJ Wirth, E Sherman, B Robinson, B Solomon, H Kang, J Lorch, F Worden, M Brose, J Patel, S Leboulleux, Y Godbert, F Barlesi, JC Morris, TK Owonikoko, DSW Tan, O Gautschi, J Weiss, la Fouchardière C de, ME Burkard, J Laskin, MH Taylor, M Kroiss, J Medioni, JW Goldman, TM Bauer, B Levy, VW Zhu, N Lakhani, V Moreno, K Ebata, M Nguyen, D Heirich, EY Zhu, X Huang, L Yang, J Kherani, SM Rothenberg, A Drilon, V Subbiah, MH Shah, ME Cabanillas. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med 2020; 383(9): 825–835 https://doi.org/10.1056/NEJMoa2005651 pmid: 32846061
21	F Griesinger, G Curigliano, M Thomas, V Subbiah, CS Baik, DSW Tan, DH Lee, D Misch, E Garralda, DW Kim, der Wekken AJ van, JF Gainor, L Paz-Ares, SV Liu, GP Kalemkerian, Y Houvras, DW Bowles, AS Mansfield, JJ Lin, V Smoljanovic, A Rahman, S Kong, A Zalutskaya, M Louie-Gao, AL Boral, J Mazières. Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial. Ann Oncol 2022; 33(11): 1168–1178 https://doi.org/10.1016/j.annonc.2022.08.002 pmid: 35973665
22	A Drilon, V Subbiah, O Gautschi, P Tomasini, F de Braud, BJ Solomon, D Shao-Weng Tan, G Alonso, J Wolf, K Park, K Goto, V Soldatenkova, S Szymczak, SS Barker, T Puri, A Bence Lin, H Loong, B Besse. Selpercatinib in patients with RET fusion-positive non-small-cell lung cancer: updated safety and efficacy from the registrational LIBRETTO-001 phase I/II trial. J Clin Oncol 2023; 41(2): 385–394 https://doi.org/10.1200/JCO.22.00393 pmid: 36122315
23	V Subbiah, PA Cassier, S Siena, E Garralda, L Paz-Ares, P Garrido, E Nadal, J Vuky, G Lopes, GP Kalemkerian, DW Bowles, M Seetharam, J Chang, H Zhang, J Green, A Zalutskaya, M Schuler, Y Fan, G Curigliano. Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial. Nat Med 2022; 28(8): 1640–1645 https://doi.org/10.1038/s41591-022-01931-y pmid: 35962206
24	V Subbiah, J Wolf, B Konda, H Kang, A Spira, J Weiss, M Takeda, Y Ohe, S Khan, K Ohashi, V Soldatenkova, S Szymczak, L Sullivan, J Wright, A Drilon. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 2022; 23(10): 1261–1273 https://doi.org/10.1016/S1470-2045(22)00541-1 pmid: 36108661
25	BJ Solomon, L Tan, JJ Lin, SQ Wong, S Hollizeck, K Ebata, BB Tuch, S Yoda, JF Gainor, LV Sequist, GR Oxnard, O Gautschi, A Drilon, V Subbiah, C Khoo, EY Zhu, M Nguyen, D Henry, KR Condroski, GR Kolakowski, E Gomez, J Ballard, AT Metcalf, JF Blake, SJ Dawson, W Blosser, LF Stancato, BJ Brandhuber, S Andrews, BG Robinson, SM Rothenberg. RET solvent front mutations mediate acquired resistance to selective RET inhibition in RET-driven malignancies. J Thorac Oncol 2020; 15(4): 541–549 https://doi.org/10.1016/j.jtho.2020.01.006 pmid: 31988000
26	JJ Lin, SV Liu, CE McCoach, VW Zhu, AC Tan, S Yoda, J Peterson, A Do, K Prutisto-Chang, I Dagogo-Jack, LV Sequist, LJ Wirth, JK Lennerz, AN Hata, M Mino-Kenudson, V Nardi, SI Ou, DSW Tan, JF Gainor. Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer. Ann Oncol 2020; 31(12): 1725–1733 https://doi.org/10.1016/j.annonc.2020.09.015 pmid: 33007380
27	V Subbiah, T Shen, SS Terzyan, X Liu, X Hu, KP Patel, M Hu, M Cabanillas, A Behrang, F Meric-Bernstam, PTT Vo, BHM Mooers, J Wu. Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations. Ann Oncol 2021; 32(2): 261–268 https://doi.org/10.1016/j.annonc.2020.10.599 pmid: 33161056
28	EY Rosen, ML Johnson, SE Clifford, R Somwar, JF Kherani, J Son, AA Bertram, MA Davare, E Gladstone, EV Ivanova, DN Henry, EM Kelley, M Lin, MSD Milan, BC Nair, EA Olek, JE Scanlon, M Vojnic, K Ebata, JF Hechtman, BT Li, LM Sholl, BS Taylor, M Ladanyi, PA Jänne, SM Rothenberg, A Drilon, GR Oxnard. Overcoming MET-dependent resistance to selective RET inhibition in patients with RET fusion-positive lung cancer by combining selpercatinib with crizotinib. Clin Cancer Res 2021; 27(1): 34–42 https://doi.org/10.1158/1078-0432.CCR-20-2278 pmid: 33082208
29	EY Rosen, HH Won, Y Zheng, E Cocco, D Selcuklu, Y Gong, ND Friedman, I de Bruijn, O Sumer, CM Bielski, C Savin, C Bourque, C Falcon, N Clarke, X Jing, F Meng, C Zimel, S Shifman, S Kittane, F Wu, M Ladanyi, K Ebata, J Kherani, BJ Brandhuber, J Fagin, EJ Sherman, N Rekhtman, MF Berger, M Scaltriti, DM Hyman, BS Taylor, A Drilon. The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers. Nat Commun 2022; 13(1): 1450 https://doi.org/10.1038/s41467-022-28848-x pmid: 35304457
30	EY Lian, SM Maritan, JG Cockburn, K Kasaian, MJ Crupi, D Hurlbut, SJ Jones, SM Wiseman, LM Mulligan. Differential roles of RET isoforms in medullary and papillary thyroid carcinomas. Endocr Relat Cancer 2017; 24(1): 53–69 https://doi.org/10.1530/ERC-16-0393 pmid: 27872141
31	K Takeuchi, M Soda, Y Togashi, R Suzuki, S Sakata, S Hatano, R Asaka, W Hamanaka, H Ninomiya, H Uehara, Y Lim Choi, Y Satoh, S Okumura, K Nakagawa, H Mano, Y Ishikawa. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012; 18(3): 378–381 https://doi.org/10.1038/nm.2658 pmid: 22327623
32	SA Jr Wells, SL Asa, H Dralle, R Elisei, DB Evans, RF Gagel, N Lee, A Machens, JF Moley, F Pacini, F Raue, K Frank-Raue, B Robinson, MS Rosenthal, M Santoro, M Schlumberger, M Shah, SG; American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma Waguespack. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25(6): 567–610 https://doi.org/10.1089/thy.2014.0335 pmid: 25810047
33	GW Krampitz, JA Norton. RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Cancer 2014; 120(13): 1920–1931 https://doi.org/10.1002/cncr.28661 pmid: 24699901
34	R Elisei, R Ciampi, A Matrone, A Prete, C Gambale, T Ramone, G Simeakis, G Materazzi, L Torregrossa, C Ugolini, C Romei. Somatic RET indels in sporadic medullary thyroid cancer: prevalence and response to selpercatinib. J Clin Endocrinol Metab 2022; 107(8): 2195–2202 https://doi.org/10.1210/clinem/dgac325 pmid: 35616103
35	N Asai, T Iwashita, M Matsuyama, M Takahashi. Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol 1995; 15(3): 1613–1619 https://doi.org/10.1128/MCB.15.3.1613 pmid: 7532281
36	I Plaza-Menacho, K Barnouin, K Goodman, RJ Martínez-Torres, A Borg, J Murray-Rust, S Mouilleron, P Knowles, NQ McDonald. Oncogenic RET kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans. Mol Cell 2014; 53(5): 738–751 https://doi.org/10.1016/j.molcel.2014.01.015 pmid: 24560924
37	RL Margraf, DK Crockett, PM Krautscheid, R Seamons, FR Calderon, CT Wittwer, R Mao. Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Hum Mutat 2009; 30(4): 548–556 https://doi.org/10.1002/humu.20928 pmid: 19177457
38	J Gao, BA Aksoy, U Dogrusoz, G Dresdner, B Gross, SO Sumer, Y Sun, A Jacobsen, R Sinha, E Larsson, E Cerami, C Sander, N Schultz. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013; 6(269): pl1 https://doi.org/10.1126/scisignal.2004088 pmid: 23550210
39	A Fusco, M Grieco, M Santoro, MT Berlingieri, S Pilotti, MA Pierotti, G Della Porta, G Vecchio. A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 1987; 328(6126): 170–172 https://doi.org/10.1038/328170a0 pmid: 3600795
40	C Romei, R Ciampi, R Elisei. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol 2016; 12(4): 192–202 https://doi.org/10.1038/nrendo.2016.11 pmid: 26868437
41	YS Ju, WC Lee, JY Shin, S Lee, T Bleazard, JK Won, YT Kim, JI Kim, JH Kang, JS Seo. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res 2012; 22(3): 436–445 https://doi.org/10.1101/gr.133645.111 pmid: 22194472
42	T Kohno, H Ichikawa, Y Totoki, K Yasuda, M Hiramoto, T Nammo, H Sakamoto, K Tsuta, K Furuta, Y Shimada, R Iwakawa, H Ogiwara, T Oike, M Enari, AJ Schetter, H Okayama, A Haugen, V Skaug, S Chiku, I Yamanaka, Y Arai, S Watanabe, I Sekine, S Ogawa, CC Harris, H Tsuda, T Yoshida, J Yokota, T Shibata. KIF5B-RET fusions in lung adenocarcinoma. Nat Med 2012; 18(3): 375–377 https://doi.org/10.1038/nm.2644 pmid: 22327624
43	D Lipson, M Capelletti, R Yelensky, G Otto, A Parker, M Jarosz, JA Curran, S Balasubramanian, T Bloom, KW Brennan, A Donahue, SR Downing, GM Frampton, L Garcia, F Juhn, KC Mitchell, E White, J White, Z Zwirko, T Peretz, H Nechushtan, L Soussan-Gutman, J Kim, H Sasaki, HR Kim, SI Park, D Ercan, CE Sheehan, JS Ross, MT Cronin, PA Jänne, PJ Stephens. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 2012; 18(3): 382–384 https://doi.org/10.1038/nm.2673 pmid: 22327622
44	F Li, Y Feng, R Fang, Z Fang, J Xia, X Han, XY Liu, H Chen, H Liu, H Ji. Identification of RET gene fusion by exon array analyses in “pan-negative” lung cancer from never smokers. Cell Res 2012; 22(5): 928–931 https://doi.org/10.1038/cr.2012.27 pmid: 22349463
45	BS Paratala, JH Chung, CB Williams, B Yilmazel, W Petrosky, K Williams, AB Schrock, LM Gay, E Lee, SC Dolfi, K Pham, S Lin, M Yao, A Kulkarni, F DiClemente, C Liu, L Rodriguez-Rodriguez, S Ganesan, JS Ross, SM Ali, B Leyland-Jones, KM Hirshfield. RET rearrangements are actionable alterations in breast cancer. Nat Commun 2018; 9(1): 4821 https://doi.org/10.1038/s41467-018-07341-4 pmid: 30446652
46	JF Gainor, AT Shaw. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 2013; 18(7): 865–875 https://doi.org/10.1634/theoncologist.2013-0095 pmid: 23814043
47	DS Richardson, TS Gujral, S Peng, SL Asa, LM Mulligan. Transcript level modulates the inherent oncogenicity of RET/PTC oncoproteins. Cancer Res 2009; 69(11): 4861–4869 https://doi.org/10.1158/0008-5472.CAN-08-4425 pmid: 19487296
48	J James, B Ruggeri, RC Armstrong, MW Rowbottom, S Jones-Bolin, RN Gunawardane, P Dobrzanski, MF Gardner, H Zhao, MD Cramer, K Hunter, RR Nepomuceno, M Cheng, D Gitnick, M Yazdanian, DE Insko, MA Ator, JL Apuy, R Faraoni, BD Dorsey, M Williams, SS Bhagwat, MW Holladay. CEP-32496: a novel orally active BRAF(V600E) inhibitor with selective cellular and in vivo antitumor activity. Mol Cancer Ther 2012; 11(4): 930–941 https://doi.org/10.1158/1535-7163.MCT-11-0645 pmid: 22319199
49	GG Li, R Somwar, J Joseph, RS Smith, T Hayashi, L Martin, A Franovic, A Schairer, E Martin, GJ Riely, J Harris, S Yan, G Wei, JW Oliver, R Patel, P Multani, M Ladanyi, A Drilon. Antitumor activity of RXDX-105 in multiple cancer types with RET rearrangements or mutations. Clin Cancer Res 2017; 23(12): 2981–2990 https://doi.org/10.1158/1078-0432.CCR-16-1887 pmid: 28011461
50	A Drilon, S Fu, MR Patel, M Fakih, D Wang, AJ Olszanski, D Morgensztern, SV Liu, BC Cho, L Bazhenova, CP Rodriguez, RC Doebele, A Wozniak, KL Reckamp, T Seery, P Nikolinakos, Z Hu, JW Oliver, D Trone, K McArthur, R Patel, PS Multani, MJ Ahn. A phase I/Ib trial of the VEGFR-sparing multikinase RET inhibitor RXDX-105. Cancer Discov 2019; 9(3): 384–395 https://doi.org/10.1158/2159-8290.CD-18-0839 pmid: 30487236
51	TK Das, RL Cagan. KIF5B-RET oncoprotein signals through a multi-kinase signaling hub. Cell Rep 2017; 20(10): 2368–2383 https://doi.org/10.1016/j.celrep.2017.08.037 pmid: 28877471
52	A Tulpule, J Guan, DS Neel, HR Allegakoen, YP Lin, D Brown, YT Chou, A Heslin, N Chatterjee, S Perati, S Menon, TA Nguyen, J Debnath, AD Ramirez, X Shi, B Yang, S Feng, S Makhija, B Huang, TG Bivona. Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules. Cell 2021; 184(10): 2649–2664.e18 https://doi.org/10.1016/j.cell.2021.03.031 pmid: 33848463
53	S Levinson, RL Cagan. Drosophila cancer models identify functional differences between RET fusions. Cell Rep 2016; 16(11): 3052–3061 https://doi.org/10.1016/j.celrep.2016.08.019 pmid: 27626672
54	C Belli, F Penault-Llorca, M Ladanyi, N Normanno, JY Scoazec, L Lacroix, JS Reis-Filho, V Subbiah, JF Gainor, V Endris, M Repetto, A Drilon, A Scarpa, F André, JY Douillard, G Curigliano. ESMO recommendations on the standard methods to detect RET fusions and mutations in daily practice and clinical research. Ann Oncol 2021; 32(3): 337–350 https://doi.org/10.1016/j.annonc.2020.11.021 pmid: 33455880
55	X Liu, T Shen, BHM Mooers, F Hilberg, J Wu. Drug resistance profiles of mutations in the RET kinase domain. Br J Pharmacol 2018; 175(17): 3504–3515 https://doi.org/10.1111/bph.14395 pmid: 29908090
56	I Dagogo-Jack, SE Stevens, JJ Lin, R Nagy, L Ferris, AT Shaw, JF Gainor. Emergence of a RET V804M gatekeeper mutation during treatment with vandetanib in RET-rearranged NSCLC. J Thorac Oncol 2018; 13(11): e226–e227 https://doi.org/10.1016/j.jtho.2018.06.021 pmid: 30368414
57	PP Knowles, J Murray-Rust, S Kjaer, RP Scott, S Hanrahan, M Santoro, CF Ibáñez, NQ McDonald. Structure and chemical inhibition of the RET tyrosine kinase domain. J Biol Chem 2006; 281(44): 33577–33587 https://doi.org/10.1074/jbc.M605604200 pmid: 16928683
58	SS Terzyan, T Shen, X Liu, Q Huang, P Teng, M Zhou, F Hilberg, J Cai, BHM Mooers, J Wu. Structural basis of resistance of mutant RET protein-tyrosine kinase to its inhibitors nintedanib and vandetanib. J Biol Chem 2019; 294(27): 10428–10437 https://doi.org/10.1074/jbc.RA119.007682 pmid: 31118272
59	PA Jänne, JC Yang, DW Kim, D Planchard, Y Ohe, SS Ramalingam, MJ Ahn, SW Kim, WC Su, L Horn, D Haggstrom, E Felip, JH Kim, P Frewer, M Cantarini, KH Brown, PA Dickinson, S Ghiorghiu, M Ranson. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015; 372(18): 1689–1699 https://doi.org/10.1056/NEJMoa1411817 pmid: 25923549
60	SS Ramalingam, J Vansteenkiste, D Planchard, BC Cho, JE Gray, Y Ohe, C Zhou, T Reungwetwattana, Y Cheng, B Chewaskulyong, R Shah, M Cobo, KH Lee, P Cheema, M Tiseo, T John, MC Lin, F Imamura, T Kurata, A Todd, R Hodge, M Saggese, Y Rukazenkov, JC; FLAURA Investigators Soria. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 2020; 382(1): 41–50 https://doi.org/10.1056/NEJMoa1913662 pmid: 31751012
61	BC Cho, B Chewaskulyong, KH Lee, A Dechaphunkul, V Sriuranpong, F Imamura, N Nogami, T Kurata, I Okamoto, C Zhou, Y Cheng, EK Cho, PJ Voon, JS Lee, H Mann, M Saggese, T Reungwetwattana, SS Ramalingam, Y Ohe. Osimertinib versus standard of care EGFR TKI as first-line treatment in patients with EGFRm advanced NSCLC: FLAURA Asian Subset. J Thorac Oncol 2019; 14(1): 99–106 https://doi.org/10.1016/j.jtho.2018.09.004 pmid: 30240852
62	V Subbiah, JF Gainor, GR Oxnard, DSW Tan, DH Owen, BC Cho, HH Loong, CE McCoach, J Weiss, YJ Kim, L Bazhenova, K Park, H Daga, B Besse, O Gautschi, C Rolfo, EY Zhu, JF Kherani, X Huang, S Kang, A Drilon. Intracranial efficacy of selpercatinib in RET fusion-positive non-small cell lung cancers on the LIBRETTO-001 trial. Clin Cancer Res 2021; 27(15): 4160–4167 https://doi.org/10.1158/1078-0432.CCR-21-0800 pmid: 34088726
63	A Drilon, JJ Lin, T Filleron, A Ni, J Milia, I Bergagnini, V Hatzoglou, V Velcheti, M Offin, B Li, DP Carbone, B Besse, T Mok, MM Awad, J Wolf, D Owen, DR Camidge, GJ Riely, N Peled, MG Kris, J Mazieres, JF Gainor, O Gautschi. Frequency of brain metastases and multikinase inhibitor outcomes in patients with RET-rearranged lung cancers. J Thorac Oncol 2018; 13(10): 1595–1601 https://doi.org/10.1016/j.jtho.2018.07.004 pmid: 30017832
64	EM Urbanska, JB Sørensen, LC Melchior, JC Costa, E Santoni-Rugiu. Durable response to combined osimertinib and pralsetinib treatment for osimertinib resistance due to novel intergenic ANK3-RET fusion in EGFR-mutated non-small-cell lung cancer. JCO Precis Oncol 2022; 6(6): e2200040 https://doi.org/10.1200/PO.22.00040 pmid: 35797511
65	Q Huang, VE Schneeberger, N Luetteke, C Jin, R Afzal, MM Budzevich, RJ Makanji, GV Martinez, T Shen, L Zhao, KM Fung, EB Haura, D Coppola, J Wu. Preclinical modeling of KIF5B-RET fusion lung adenocarcinoma. Mol Cancer Ther 2016; 15(10): 2521–2529 https://doi.org/10.1158/1535-7163.MCT-16-0258 pmid: 27496134
66	T Shen, X Hu, X Liu, V Subbiah, BHM Mooers, J Wu. The L730V/I RET roof mutations display different activities toward pralsetinib and selpercatinib. NPJ Precis Oncol 2021; 5(1): 48 https://doi.org/10.1038/s41698-021-00188-x pmid: 34099825
67	JJ Lin, JF Gainor. An early look at selective RET inhibitor resistance: new challenges and opportunities. Br J Cancer 2021; 124(11): 1757–1758 https://doi.org/10.1038/s41416-021-01344-7 pmid: 33758332
68	V Subbiah, T Shen, M Tetzlaff, A Weissferdt, LA Byers, T Cascone, A Behrang, F Meric-Bernstam, BHM Mooers, SM Rothenberg, K Ebata, J Wu. Patient-driven discovery and post-clinical validation of NTRK3 fusion as an acquired resistance mechanism to selpercatinib in RET fusion-positive lung cancer. Ann Oncol 2021; 32(6): 817–819 https://doi.org/10.1016/j.annonc.2021.02.010 pmid: 33617938
69	VW Zhu, R Madison, AB Schrock, SI Ou. Emergence of High Level of MET Amplification as off-target resistance to selpercatinib treatment in KIF5B-RET NSCLC. J Thorac Oncol 2020; 15(7): e124–e127 https://doi.org/10.1016/j.jtho.2020.03.020 pmid: 32593453
70	A Drilon, E Rogers, D Zhai, W Deng, X Zhang, D Lee, J Ung, J Whitten, H Zhang, J Liu, T Hu, H Zhuang, Y Lu, Z Huang, A Braber, Z Zimmerman, R Xin, J Cui, V Subbiah. TPX-0046 is novel and potent RET/SRC inhibitor for RET-driven cancers. Ann Oncol 2019; 30(ESMO abstract): 506P
71	AE Drilon, D Zhai, E Rogers, W Deng, X Zhang, J Ung, D Lee, L Rodon, A Graber, ZF Zimmerman, BW Murray, V Subbiah. The next-generation RET inhibitor TPX-0046 is active in drug-resistant and naïve RET-driven cancer models. J Clin Oncol 2020; 38(15 suppl): 3616 https://doi.org/10.1200/JCO.2020.38.15_suppl.3616
72	M Repetto, E Crimini, L Ascione, L Boscolo Bielo, C Belli, G Curigliano. The return of RET GateKeeper mutations? An in-silico exploratory analysis of potential resistance mechanisms to novel RET macrocyclic inhibitor TPX-0046. Invest New Drugs 2022; 40(5): 1133–1136 https://doi.org/10.1007/s10637-022-01259-x pmid: 35612671
73	NA Pennell, LJ Wirth, JF Gainor, JK Rotow, ML Johnson, TM Bauer, M Kroiss, V Sukrithan, H Kang, FP Worden, CM Bestvina, J Hadoux, PA Cassier, A Italiano, J Wolf, MS Brose, E Avsar, MD Axelson, V Subbiah, AE Drilon. A first-in-human phase 1 study of the next-generation RET inhibitor, LOXO-260, in RET inhibitor refractory patients with RET-altered cancers (trial in progress). J Clin Oncol 2022; 40(suppl 16): TPS8595
74	I MiyazakiK IshidaM KatoT SuzukiH Fujita S OhkuboY Iwasawa. Discovery of TAS0953/HM06, a novel next generation RET-specific inhibitor capable of inhibiting RET solvent front mutations. AACR-NCI-EORTC Virtual International Conference 2021; October 7–10
75	P Schoffski, BC Cho, A Italiano, HHF Loong, C Massard, LM Rodriguez, JY Shih, V Subbiah, L Verlingue, K Andreas, CT Basson, A Clawson, PTC Ho, S Knight, A Scheuber, M Keegan. BOS172738, a highly potent and selective RET inhibitor, for the treatment of RET-altered tumors including RET-fusion+ NSCLC and RET-mutant MTC: phase 1 study results. J Clin Oncol 2021; 39(15 suppl): 3008 https://doi.org/10.1200/JCO.2021.39.15_suppl.3008
76	V Subbiah, J Zhong, Y Lu, Y Liu, M Chen, X Chen, H Wang, J Zhu, S Lu, AE Drilon. The development of APS03118, a potent next-generation RET inhibitor for treating RET-inhibitor-resistant patients. J Clin Oncol 2022; 40(16 suppl): e15107 https://doi.org/10.1200/JCO.2022.40.16_suppl.e15107

[1]

FMD-23004-OF-WJ_suppl_1

Download

[1]	Jia Zhong, Hua Bai, Zhijie Wang, Jianchun Duan, Wei Zhuang, Di Wang, Rui Wan, Jiachen Xu, Kailun Fei, Zixiao Ma, Xue Zhang, Jie Wang. Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future directions[J]. Front. Med., 2023, 17(1): 18-42.
[2]	Hongyi Wang, Zhuochao Liu, Jun Wang, Fangqiong Hu, Qi Zhou, Li Wei, Qiyuan Bao, Jizhuang Wang, Jing Liang, Zhihong Liu, Weibin Zhang. Superenhancers activate the autophagy-related genes Beclin1 and LC3B to drive metastasis and drug resistance in osteosarcoma[J]. Front. Med., 2022, 16(6): 883-895.
[3]	Jianhua Shi, Ying Cheng, Qiming Wang, Kai Li, Lin Wu, Baohui Han, Gongyan Chen, Jianxing He, Jie Wang, Haifeng Qin, Xiaoling Li. Anlotinib as third- or further-line therapy for short-term relapsed small-cell lung cancer: subgroup analysis of a randomized phase 2 study (ALTER1202)[J]. Front. Med., 2022, 16(5): 766-772.
[4]	Shi-Yong Sun. Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors[J]. Front. Med., 2022, 16(5): 701-713.
[5]	Xiang Wang, Minghui Wang, Lin Feng, Jie Song, Xin Dong, Ting Xiao, Shujun Cheng. Four-protein model for predicting prognostic risk of lung cancer[J]. Front. Med., 2022, 16(4): 618-626.
[6]	Yaru Tian, Hairong Tian, Xiaoyang Zhai, Hui Zhu, Jinming Yu. Bevacizumab in combination with pemetrexed and platinum for elderly patients with advanced non-squamous non-small-cell lung cancer: a retrospective analysis[J]. Front. Med., 2022, 16(4): 610-617.
[7]	Fang Huang, Yanwen Cui, He Yan, Hui Liu, Xiangrui Guo, Guangze Wang, Shuisen Zhou, Zhigui Xia. *Prevalence of antifolate drug resistance markers in Plasmodium vivax* in China**[J]. Front. Med., 2022, 16(1): 83-92.
[8]	Wenjing Zhou, Jing Zhang, Mingkun Yan, Jin Wu, Shuo Lian, Kang Sun, Baiqing Li, Jia Ma, Jun Xia, Chaoqun Lian. Orlistat induces ferroptosis-like cell death of lung cancer cells[J]. Front. Med., 2021, 15(6): 922-932.
[9]	Na Qin, Yuancheng Li, Cheng Wang, Meng Zhu, Juncheng Dai, Tongtong Hong, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Gary Goodman, Stig E. Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, H-Erich Wichmann, Heike Bickeboller, Gadi Rennert, Susanne Arnold, Paul Brennan, John K. Field, Sanjay Shete, Loic Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Rayjean J. Hung, Angeline Andrew, Lambertus A. Kiemeney, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Penella Woll, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Victoria L. Stevens, Guangfu Jin, David C. Christiani, Zhibin Hu, Christopher I. Amos, Hongxia Ma, Hongbing Shen. Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma[J]. Front. Med., 2021, 15(2): 275-291.
[10]	Jiahui Xu, Qianqian Wang, Elaine Lai Han Leung, Ying Li, Xingxing Fan, Qibiao Wu, Xiaojun Yao, Liang Liu. Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer[J]. Front. Med., 2020, 14(1): 60-67.
[11]	Shengfen Wang, Yang Zhou, Bing Zhao, Xichao Ou, Hui Xia, Yang Zheng, Yuanyuan Song, Qian Cheng, Xinyang Wang, Yanlin Zhao. Characteristics of compensatory mutations in the rpoC gene and their association with compensated transmission of Mycobacterium tuberculosis[J]. Front. Med., 2020, 14(1): 51-59.
[12]	Zhao Zhang, Jun Jiang, Xiaodong Wu, Mengyao Zhang, Dan Luo, Renyu Zhang, Shiyou Li, Youwen He, Huijie Bian, Zhinan Chen. Chimeric antigen receptor T cell targeting EGFRvIII for metastatic lung cancer therapy[J]. Front. Med., 2019, 13(1): 57-68.
[13]	Liqin Wang, Rene Bernards. Taking advantage of drug resistance, a new approach in the war on cancer[J]. Front. Med., 2018, 12(4): 490-495.
[14]	Kohei Miyazono, Yoko Katsuno, Daizo Koinuma, Shogo Ehata, Masato Morikawa. Intracellular and extracellular TGF-β signaling in cancer: some recent topics[J]. Front. Med., 2018, 12(4): 387-411.
[15]	Dalin Zhang, Liwei Qu, Bo Zhou, Guizhen Wang, Guangbiao Zhou. Genomic variations in the counterpart normal controls of lung squamous cell carcinomas[J]. Front. Med., 2018, 12(3): 280-288.

Viewed

Full text

Abstract

Cited

Shared

Discussed