Abstract 2897: Discovery and characterization of driver MAPK and PI3K pathway mutations in tumors and association with drug response in cell lines.
Authors: Tomilo Mark , Williams Paul D. , Bowden Emma T. , Gajjala Supra R. , Bandla Santhoshi , Eddy Sean F. , Sadis Seth E. , Wyngaard Peter J. , Khazanov Nickolay A. , Rhodes Daniel R. 
Published: August 2014

The MAPK and PI3K pathways are frequently altered in human cancer and are targeted by dozens of agents in clinical trials. The successful application of these therapies, alone or in combination, may depend on the activation status of both pathways. Next-generation sequencing of cancer exomes provides a unique opportunity to systematically survey pathway alterations in cancer. Using somatic mutation data obtained from The Cancer Genome Atlas, we sought to catalog the members of the MAPK and PI3K pathways with driver mutations, the frequency of occurrence in common cancers and the frequency of co-occurrence. Furthermore, we sought to characterize the association of pathway mutation status with drug response in pre-clinical models.

While the MAPK and PI3K pathways were frequently altered, the frequency of single and dual pathway alteration and the altered genes varied substantially across cancer types. The MAPK pathway was most frequently altered in rectal (62%), colon (59%), uterine (31%) and lung adenocarcinoma (45%) but infrequently altered in and breast cancer (4%). KRAS, BRAF and NRAS hotspot mutations were the most common pathway drivers, along with NF1 deleterious mutations in certain cancer types. The PI3K pathway was most frequently altered in uterine (84%), breast (40%) and glioblastoma (41%) but was rarely altered in lung adenocarcinoma (9%). Hotspot mutations in PIK3CA and hotspot and deleterious mutations in PTEN were the most common pathway alterations. In addition, predicted driver mutations occurred in PIK3R1, PIK3R3, MTOR, AKT1 and AKT3. Notably, MAPK and PI3K pathway alterations co-occurred in uterine (30%), colon (17%) and gastric (12%) cancers more so than would be expected by chance (p &lt; 0.02). In contrast, other cancer types favored one pathway almost exclusively and thus had little co-occurrence. For example, breast cancer significantly favored PI3K pathway whereas lung adenocarcinoma favored MAPK pathway.

To assess the effect of pathway mutation status on treatment response, we integrated hybrid-capture sequencing data from the Cancer Cell Line Encyclopedia with pharmacological data from over 150 compounds. We found that MAPK and PI3K pathway mutations most significantly associated with sensitivity to MEK and PI3K/AKT/mTOR inhibitors, respectively. Notably though, cell lines with co-occurring MAPK pathway and PIK3CA mutations were insensitive to MEK inhibitors and cell lines with co-occurring PI3K pathway and KRAS mutations were insensitive to PI3K inhibitors. Also, not all pathway mutations conferred equal sensitivity. For example, BRAF mutants were generally sensitive, KRAS mutants were mixed and NF1 mutants were generally insensitive to MEK inhibitors. Taken together, our work highlights the need to consider pathways and co-occurrence in the development of targeted therapies.

Citation Format: Mark Tomilo, Paul D. Williams, Emma T. Bowden, Supra R. Gajjala, Santhoshi Bandla, Sean F. Eddy, Seth E. Sadis, Peter J. Wyngaard, Nickolay A. Khazanov, Daniel R. Rhodes. Discovery and characterization of driver MAPK and PI3K pathway mutations in tumors and association with drug response in cell lines. [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 2897. doi:10.1158/1538-7445.AM2013-2897