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Ref Type Journal Article
PMID (26831717)
Authors Kwiatkowski DJ, Choueiri TK, Fay AP, Rini BI, Thorner AR, de Velasco G, Tyburczy ME, Hamieh L, Albiges L, Agarwal N, Ho TH, Song J, Pignon JC, Barrios PM, Michaelson MD, Van Allen EM, Krajewski KM, Porta C, Pal SK, Bellmunt J, McDermott DF, Heng DY, Gray KP, Signoretti S
Title Mutations in TSC1, TSC2, and MTOR Are Associated with Response to Rapalogs in Patients with Metastatic Renal Cell Carcinoma.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 10
Date 2016 May 15
URL
Abstract Text We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC).We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response.Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response.In this cohort of mRCC patients, mutations in MTOR, TSC1, or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (24 of 43, 56%) had no mTOR pathway mutation identified. Clin Cancer Res; 22(10); 2445-52. ©2016 AACRSee related commentary by Voss and Hsieh, p. 2320.

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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
PTEN L70H missense unknown PTEN L70H lies within the phosphatase tensin-type domain of the Pten protein (UniProt.org). L70H has been identified in sequencing studies (PMID: 26831717), but has not been biochemically characterized and therefore, its effect on Pten protein function is unknown (PubMed, Aug 2021).
VHL N131Y missense unknown VHL N131Y lies within the CCT complex-binding region of the Vhl protein (UniProt.org). N131Y has been identified in the scientific literature (PMID: 24727139, PMID: 29172931, PMID: 26831717), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Oct 2021).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TSC1 inact mut renal cell carcinoma predicted - sensitive Temsirolimus Clinical Study - Cohort Actionable In a retrospective analysis, 28% (12/43) of metastatic renal cell carcinoma patients who responded to rapalogs, Afinitor (everolimus) or Torisel (temsirolimus), harbored inactivating TSC1, TSC2 mutations and/or activating MTOR mutations, compared to 11% (4/36) in patients who did not respond to therapy (PMID: 26831717). 26831717
TSC1 inact mut renal cell carcinoma predicted - sensitive Everolimus Clinical Study - Cohort Actionable In a retrospective analysis, 28% (12/43) of metastatic renal cell carcinoma patients who responded to rapalogs, Afinitor (everolimus) or Torisel (temsirolimus), harbored inactivating TSC1, TSC2 mutations and/or activating MTOR mutations, compared to 11% (4/36) in patients who did not respond to therapy (PMID: 26831717). 26831717
TSC2 inact mut renal cell carcinoma predicted - sensitive Temsirolimus Clinical Study - Cohort Actionable In a retrospective analysis, 28% (12/43) of metastatic renal cell carcinoma patients who responded to rapalogs, Afinitor (everolimus) or Torisel (temsirolimus), harbored inactivating TSC1, TSC2 mutations and/or activating MTOR mutations, compared to 11% (4/36) in patients who did not respond to therapy (PMID: 26831717). 26831717
TSC2 inact mut renal cell carcinoma predicted - sensitive Everolimus Clinical Study - Cohort Actionable In a retrospective analysis, 28% (12/43) of metastatic renal cell carcinoma patients who responded to rapalogs, Afinitor (everolimus) or Torisel (temsirolimus), harbored inactivating TSC1, TSC2 mutations and/or activating MTOR mutations, compared to 11% (4/36) in patients who did not respond to therapy (PMID: 26831717). 26831717