Mutations in TSC1, TSC2, and MTOR Are Associated with Response to Rapalogs in Patients with Metastatic Renal Cell Carcinoma.

Abstract

PURPOSE:

We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC).

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: David J Kwiatkowski, Toni K Choueiri, André P Fay, Brian I Rini, Aaron R Thorner, Guillermo de Velasco, Magdalena E Tyburczy, Lana Hamieh, Laurence Albiges, Neeraj Agarwal, Thai H Ho, Jiaxi Song, Jean-Christophe Pignon, Pablo M Barrios, M Dror Michaelson, Eliezer Van Allen, Katherine M Krajewski, Camillo Porta, Sumanta Pal, Joaquim Bellmunt, David F McDermott, Daniel Y C Heng, Kathryn P Gray, Sabina Signoretti
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 10 Pg. 2445-2452 (05 15 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 26831717 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• DNA, Neoplasm
• Protein Kinase Inhibitors
• TSC1 protein, human
• TSC2 protein, human
• Tuberous Sclerosis Complex 1 Protein
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Aged
• Carcinoma, Renal Cell (drug therapy, genetics)
• Cohort Studies
• DNA, Neoplasm (genetics)
• Female
• Humans
• Kidney Neoplasms (drug therapy, genetics)
• Male
• Middle Aged
• Mutation (genetics)
• Protein Kinase Inhibitors (therapeutic use)
• Signal Transduction (genetics)
• TOR Serine-Threonine Kinases (genetics)
• Tuberous Sclerosis Complex 1 Protein
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (genetics)