The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers

Ezra Y. Rosen, Helen H. Won, Youyun Zheng, Emiliano Cocco, Duygu Selcuklu, Yixiao Gong, Noah D. Friedman, Ino Bruijn, Onur Sumer, Craig M. Bielski, Casey Savin, Caitlin Bourque, Christina Falcon, Nikeysha Clarke, Xiaohong Jing, Fanli Meng, Catherine Zimel, Sophie Shifman, Srushti Kittane, Fan Wu, Marc Ladanyi, Kevin Ebata, Jennifer Kherani, Barbara J. Brandhuber, James Fagin, Eric J. Sherman, Natasha Rekhtman, Michael F. Berger, Maurizio Scaltriti, David M. Hyman, Barry S. Taylor () and Alexander Drilon ()
Additional contact information
Ezra Y. Rosen: Memorial Sloan Kettering Cancer Center
Helen H. Won: Memorial Sloan Kettering Cancer Center
Youyun Zheng: Memorial Sloan Kettering Cancer Center
Emiliano Cocco: Memorial Sloan Kettering Cancer Center
Duygu Selcuklu: Memorial Sloan Kettering Cancer Center
Yixiao Gong: Memorial Sloan Kettering Cancer Center
Noah D. Friedman: Memorial Sloan Kettering Cancer Center
Ino Bruijn: Memorial Sloan Kettering Cancer Center
Onur Sumer: Memorial Sloan Kettering Cancer Center
Craig M. Bielski: Memorial Sloan Kettering Cancer Center
Casey Savin: Memorial Sloan Kettering Cancer Center
Caitlin Bourque: Memorial Sloan Kettering Cancer Center
Christina Falcon: Memorial Sloan Kettering Cancer Center
Nikeysha Clarke: Memorial Sloan Kettering Cancer Center
Xiaohong Jing: Memorial Sloan Kettering Cancer Center
Fanli Meng: Memorial Sloan Kettering Cancer Center
Catherine Zimel: Memorial Sloan Kettering Cancer Center
Sophie Shifman: Memorial Sloan Kettering Cancer Center
Srushti Kittane: Memorial Sloan Kettering Cancer Center
Fan Wu: Memorial Sloan Kettering Cancer Center
Marc Ladanyi: Memorial Sloan Kettering Cancer Center
Kevin Ebata: Loxo Oncology at Lilly
Jennifer Kherani: Loxo Oncology at Lilly
Barbara J. Brandhuber: Loxo Oncology at Lilly
James Fagin: Memorial Sloan Kettering Cancer Center
Eric J. Sherman: Memorial Sloan Kettering Cancer Center
Natasha Rekhtman: Memorial Sloan Kettering Cancer Center
Michael F. Berger: Memorial Sloan Kettering Cancer Center
Maurizio Scaltriti: Memorial Sloan Kettering Cancer Center
David M. Hyman: Loxo Oncology at Lilly
Barry S. Taylor: Memorial Sloan Kettering Cancer Center
Alexander Drilon: Memorial Sloan Kettering Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: Abstract The efficacy of the highly selective RET inhibitor selpercatinib is now established in RET-driven cancers, and we sought to characterize the molecular determinants of response and resistance. We find that the pre-treatment genomic landscape does not shape the variability of treatment response except for rare instances of RAS-mediated primary resistance. By contrast, acquired selpercatinib resistance is driven by MAPK pathway reactivation by one of two distinct routes. In some patients, on- and off-target pathway reactivation via secondary RET solvent front mutations or MET amplifications are evident. In other patients, rare RET-wildtype tumor cell populations driven by an alternative mitogenic driver are selected for by treatment. Multiple distinct mechanisms are often observed in the same patient, suggesting polyclonal resistance may be common. Consequently, sequential RET-directed therapy may require combination treatment with inhibitors targeting alternative MAPK effectors, emphasizing the need for prospective characterization of selpercatinib-treated tumors at the time of monotherapy progression.

Date: 2022
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DOI: 10.1038/s41467-022-28848-x

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