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Ref Type Journal Article
PMID (35304457)
Authors Rosen EY, Won HH, Zheng Y, Cocco E, Selcuklu D, Gong Y, Friedman ND, de Bruijn I, Sumer O, Bielski CM, Savin C, Bourque C, Falcon C, Clarke N, Jing X, Meng F, Zimel C, Shifman S, Kittane S, Wu F, Ladanyi M, Ebata K, Kherani J, Brandhuber BJ, Fagin J, Sherman EJ, Rekhtman N, Berger MF, Scaltriti M, Hyman DM, Taylor BS, Drilon A
Title The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers.
Journal Nature communications
Vol 13
Issue 1
Date 2022 Mar 18
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
RET L870F missense unknown RET L870F lies within the protein kinase domain of the Ret protein (UniProt.org). L870F has been identified in sequencing studies (PMID: 35304457), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, May 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET V804M RET Y806C RET M918T Advanced Solid Tumor predicted - resistant Selpercatinib Preclinical - Biochemical Actionable In a preclinical study, transformed human cells expressing RET M918T, V804M, and Y806C in cis were resistant to Retevmo (selpercatinib) in culture (PMID: 35304457). 35304457
RET V804M RET Y806C Advanced Solid Tumor decreased response Selpercatinib Preclinical - Biochemical Actionable In a preclinical study, transformed human cells expressing RET V804M and Y806C in cis were less sensitive to Retevmo (selpercatinib) in culture (PMID: 35304457). 35304457