Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Nature communications	13	1	2022 Mar 18	1450	Nat Commun

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, Dec 2023).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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