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|Ref Type||Journal Article|
|Authors||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 SJ, Blosser W, Stancato LF, Brandhuber BJ, Andrews S, Robinson BG, Rothenberg SM|
|Title||RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies.|
|Journal||Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer|
|Date||2020 Jan 24|
|Abstract Text||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.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.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 multikinase inhibitors and selective RET TKIs.RET G810 solvent front mutations represent the first described recurrent mechanism of resistance to selective RET inhibition with selpercatinib. Development of potent inhibitor of these mutations and maintaining activity against RET gatekeeper mutations could be an effective strategy to target resistance to selective RET inhibitors.|
|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||G810C||missense||unknown||RET G810C lies within the protein kinase domain of the Ret protein (UniProt.org). G810C is associated with RET inhibitor resistance in the context of RET fusions (PMID: 31988000, PMID: 33161056), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2022).||Y|
|RET||G810R||missense||unknown||RET G810R lies within the protein kinase domain of the Ret protein (UniProt.org). G810R is associated with RET inhibitor resistance in the context of RET fusions (PMID: 31988000, PMID: 33161056, PMID: 34373541), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2022).||Y|
|RET||G810S||missense||unknown||RET G810S lies within the protein kinase domain of the Ret protein (UniProt.org). G810S has been demonstrated to confer resistance to tyrosine kinase inhibitors in the context of RET fusions (PMID: 29908090, PMID: 31988000), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Nov 2021).||Y|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|RET V804M RET G810S RET L881V RET M918T||thyroid gland medullary carcinoma||predicted - resistant||Selpercatinib||Case Reports/Case Series||Actionable||In a clinical case study, a patient with hereditary medullary thyroid carcinoma harboring germline RET M918T demonstrated disease progression following an initial response to Retevmo (selpercatinib), and ctDNA sequencing revealed a decrease in RET L881V, but an increase in RET V804M and RET G810S (PMID: 31988000).||31988000|