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3. Preclinical activity of NVL-655 in patient-derived models of ALK cancers, including those with lorlatinib-resistant G1202R/L1196M compound mutation

Author

Fujino, T., primary, Nguyen, L., additional, Yoda, S., additional, Yu, M., additional, Mizuta, H., additional, Bigot, L., additional, Nobre, C., additional, Tangpeerachaikul, A., additional, Pelish, H.E., additional, Friboulet, L., additional, Lee, J., additional, Cho, B., additional, and Hata, A.N., additional

Published
2022
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11. RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies

Author

Solomon, BJ, Tan, L, Lin, JJ, Wong, SQ, Hollizeck, S, Ebata, K, Tuch, BB, Yoda, S, Gainor, JF, Sequist, LV, Oxnard, GR, Gautschi, O, Drilon, A, Subbiah, V, Khoo, C, Zhu, EY, Nguyen, M, Henry, D, Condroski, KR, Kolakowski, GR, Gomez, E, Ballard, J, Metcalf, AT, Blake, JF, Dawson, S-J, Blosser, W, Stancato, LF, Brandhuber, BJ, Andrews, S, Robinson, BG, Rothenberg, SM, Solomon, BJ, Tan, L, Lin, JJ, Wong, SQ, Hollizeck, S, Ebata, K, Tuch, BB, Yoda, S, Gainor, JF, Sequist, LV, Oxnard, GR, Gautschi, O, Drilon, A, Subbiah, V, Khoo, C, Zhu, EY, Nguyen, M, Henry, D, Condroski, KR, Kolakowski, GR, Gomez, E, Ballard, J, Metcalf, AT, Blake, JF, Dawson, S-J, Blosser, W, Stancato, LF, Brandhuber, BJ, Andrews, S, Robinson, BG, and Rothenberg, SM

Abstract

INTRODUCTION: Novel rearranged in transfection (RET)-specific tyrosine kinase inhibitors (TKIs) such as selpercatinib (LOXO-292) have shown unprecedented efficacy in tumors positive for RET fusions or mutations, notably RET fusion-positive NSCLC and RET-mutated medullary thyroid cancer (MTC). However, the mechanisms of resistance to these agents have not yet been described. METHODS: Analysis was performed of circulating tumor DNA and tissue in patients with RET fusion-positive NSCLC and RET-mutation positive MTC who developed disease progression after an initial response to selpercatinib. Acquired resistance was modeled preclinically using a CCDC6-RET fusion-positive NSCLC patient-derived xenograft. The inhibitory activity of anti-RET multikinase inhibitors and selective RET TKIs was evaluated in enzyme and cell-based assays. RESULTS: After a dramatic initial response to selpercatinib in a patient with KIF5B-RET NSCLC, analysis of circulating tumor DNA revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front before the emergence of clinical resistance. Postmortem biopsy studies reported intratumor and intertumor heterogeneity with distinct disease subclones containing G810S, G810R, and G810C mutations in multiple disease sites indicative of convergent evolution on the G810 residue resulting in a common mechanism of resistance. Acquired mutations in RET G810 were identified in tumor tissue from a second patient with CCDC6-RET fusion-positive NSCLC and in plasma from patients with additional RET fusion-positive NSCLC and RET-mutant MTC progressing on an ongoing phase 1 and 2 trial of selpercatinib. Preclinical studies reported the presence of RET G810R mutations in a CCDC6-RET patient-derived xenograft (from a patient with NSCLC) model of acquired resistance to selpercatinib. Structural modeling predicted that these mutations sterically hinder the binding of selpercatinib, and in vitro assays confirmed loss of activity for both anti-RET mul

Published
2020

13. 10th Annual scientific session September 29–October 2, 2005 Seattle, Washington

Author

Hacker, M, Jakobs, T, Matthiesen, F, Vollmar, C, Nikolaou, K, Becker, C, Knez, A, Pfluger, T, Tiling, R, Hahn, K, Iwanochko, RM, Petrovici, R, Lee, DS, Husain, M, Woo, A, Siu, S, Masry, HZ El, Jaradat, Z, Khan, BR, Kalaria, VG, Mahenthiran, J, Raiesdana, A, Sawada, SG, Shah, DP, Virnich, DE, Ward, RP, Gundeck, EL, Williams, KA, Spencer, KT, Lang, RM, Akutsu, Y, Gewirtz, H, Gregory, SA, Zervos, GD, Thomas, GS, Yasuda, T, Duvall, WL, Croft, LB, Pungoti, C, Henzlova, MJ, Hage, FG, Heo, J, Iskandrian, AE, Johnson, NP, Leonard, SM, Kansal, P, Wu, E, Holly, TA, Michelena, HI, Stepnowski, D, Frain, V, Dempsey, DT, Kowalski, C, Van Decker, WA, Smanio, P, Rodrigues, F, Meneghelo, R, Mastrocolla, L, Thorn, A, Piegas, L, Beraldo, P, Mello, R, Tebexreni, S, ten Cate, TJF, Visser, FC, Panhuyzen-Goedkoop, NM, Verzijlbergen, JF, van Hemel, NM, Thompsen, J, Athar, H, Sainani, V, O’Sullivan, D, Leka, I, Heller, GV, Jansen, M, Grasman, M, Stier, A, Konnann, O, Silva, JA, Vitola, JV, Cunha, C, Cerci, MS, Ribeiro, OF, Jansen, MHA, Grasman, ME, Zukovski, T, Mickevicz, C, Visser, F, Snyder, K, Polepalle, D, Nichols, KJ, Dim, U, Akinboboye, OO, Vijay Anand, D, Lim, E, Nagar, K, Raval, U, Lahiri, A, Elhendy, A, Huurman, A, Schinkel, AF, Bax, JJ, van Domburg, RT, Valkema, R, Poldermans, D, Heiba, SI, Katzel, JA, Altinyay, E, Milarodovic, R, Castellon, I, Raphael, B, Abdel-Dayem, HA, Coppola, J, Heston, TF, Høilund-Carlsen, PF, Johansen, A, Vach, W, Christensen, HW, Møldrup, M, Haghfelt, T, Kumar, A, Stricker, S, Das, MK, Oddis, CV, Byrne, D, Myers, JS, Churchwell, AL, Churchwell, KB, Nichols, KJ, Dim, U, Wang, Y, Akinboboye, OO, Bergmann, SR, Druz, RS, Gopal, AS, Borges, A, Ngai, K, Chen, J, Caputlu-Wilson, SF, Shi, H, Galt, JR, Faber, TL, Garcia, EV, Cole, V, Habtemarkos, R, Sun, L, Lacy, J, Kjaer, A, Cortsen, A, Federspiel, M, Holm, S, O’Connor, M, Hesse, B, Lewin, HC, Hyun, MC, Carboni, GP, Tavolozza, M, Fukuzawa, S, Ozawa, S, Inagaki, M, Sugioka, J, Okino, S, Ichikawa, S, Mohart, JM, Fairlamb, JE, Hutter, AJ, Gutierrez, FR, Zheng, J, Lesniak, DM, Gropler, RJ, Woodard, PK, Santana, C, Esteves, FP, Lerakis, S, Halkar, R, Narla, R, Santana, CA, Alvarez, A, Halkar, RK, Chen, S, Yao, Z, Ramrakhiani, S, Safadi, AH, Foltz, JM, Stricker, SL, Williams, AA, Grewal, KS, George, PB, Richards, DR, Calnon, DA, Bhama, A, Goetze, S, Wahl, RL, Elmquist, T, Mazzara, J, Hsu, BL, Moser, KW, Bateman, TM, Stoner, C, Case, JA, Matsumoto, N, Sato, Y, Yoda, S, Muromoto, M, Nalamolu, VRP, Patel, RN, Dias, JK, Kaminski, RJ, Kersey, TW, Robinson, VJB, Oaknin, JH, Shwartz, SC, Pagnanelli, RA, Coleman, RE, Borges-Neto, S, Cullom, SJ, Noble, GL, Masse, M, McGhie, AI, Friedman, JD, Devabhaktuni, M, Hickey, KT, Sciacca, RR, Giedd, KN, Johnson, U, Bokhari, S, Nemirovsky, D, Machac, J, Almeida, D, Kanayama, S, Satake, O, Kajinami, K, Hertenstein, GK, Volker, LL, Verdes, L, Folks, RD, Clements, IP, Mullan, BP, Breen, JF, McGregor, CG, Côté, C, Dumont, M, Lefebvre, J, Poirier, L, Lacourcière, Y, Gupta, R, Aqel, RA, Mehta, D, Clay, MA, Zoghbi, G, Hwang, K-H, Kim, J-H, Choe, W, Kim, N-B, Khateeb, R, Keefer, PM, Vedala, G, Mahajan, NM, Shetty, VS, Thekkott, DT, Hollander, GH, Greengart, AG, Shani, JS, Lichstein, EL, Raza, M, Panjrath, G, Meesala, M, Ghanbarinia, A, Jain, D, Seo, I, Del Priore, E, Almonte, A, Kappes, R, Fedida, A, Ong, K, Kritzman, JN, Dey, S, Corbett, JR, Ficaro, EP, Stowers, SA, Tomlinson, GC, Cunningham, MS, Guilarte, NM, Carrio, I, Lundbye, JB, Katten, D, Ahlberg, A, Boden, WE, Cyr, G, Paiesdana, A, and Murthy, DR

Published
2005
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30. An XPS investigation on the influence of the substrate and growth conditions on pyrite thin films surface composition

Author

Morales C., Flores E., Yoda S., Niño M.A., Martín y Marero D., Soriano L., Rojo J., Ares J.R., Ferrer I.J., Sánchez C. and The authors thank technical support from Mr. F. Moreno. Financial support by MINECO-FEDER ( MAT2015-65203R ) is acknowledged and the project INFANTE ( PIE 201550E072 ) is also recognized. Carlos Morales thanks the Ministerio de Educación Cultura y Deporte of Spain for the FPU grant.

Published
2019

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