Abstract 3515: Pathway convergent evolution underscores treatment response to MTOR inhibitors in kidney cancers.

Abstract

Abstract Despite the established role of MTOR inhibitors (rapalogs) in treating advanced kidney cancer, therapeutic benefit varies and predictive biomarkers are lacking. Intratumor branching heterogeneity, a recently discovered hallmark of this disease, has raised concerns about the feasibility of developing genomic biomarkers for targeted agents in kidney cancer. We undertook an outlier approach to interrogate the genetic determinants underlying long-term therapeutic response (>20 months) to rapalogs in 6 patients. An integrated ultra-deep targeted-exome (∼500x) and standard whole-exome (∼100x) sequencing was performed. Additionally, to address intratumor and intertumor heterogeneity, spatially separated tumor specimens from the same individuals were analyzed whenever possible. Multiregional sequencing unveiled surprising MTOR pathway convergent evolution, manifested by MTOR pathway activation by means of distinct genomic events in spatially separate sites of disease within the same individual. Amongst the core components of the MTORC1 pathway, complete functional loss of TSC1 and TSC2, and a hyperactive MTOR mutant were discovered in 4 of 6 long-term responders. Mutations in MTOR Clustered at FAT and kinase domains confer hyperactivity and yet remain sensitive to rapamycin. Here, we affirm intratumor heterogeneity, identify genomic determinants of drug response, and discover pathway convergent evolution in the majority of long-term responders. We propose a “river” model in which intratumor and intertumor clonal heterogeneity in cancer patients evolves like a branching river that converges at critical nodes. These convergent points provide unique opportunities for the treatment of genetically diverged yet functionally converged cancers in any given patient. Citation Format: Martin H. Voss, A Ari Hakimi, Can G. Pham, A Rose Brannon, Ying-Bei Chen, Luis F. Cunha, Oguz Akin, Han Liu, Shugaku Takeda, Sasinya N. Scott, Nicholas D. Socci, Agnes Viale, Nikolaus Schultz, Chris Sander, Victor E. Reuter, Paul Russo, Emily H. Cheng, Robert J. Motzer, Michael F. Berger, James J. Hsieh. Pathway convergent evolution underscores treatment response to MTOR inhibitors in kidney cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3515. doi:10.1158/1538-7445.AM2013-3515