Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	22	10	2016 May 15	2445-2452	Clin Cancer Res

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, Jun 2024).
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, May 2024).

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