Abstract A2-52: Pan-cancer analysis reveals distinct effects of receptor tyrosine kinase mutations on downstream pathway activities
Authors: Morozova Olena , Ng Sam , Rao Arjun , Stuart Josh , Haussler David , Salama Sofie 
Published: November 2015

Receptor tyrosine kinases (RTKs) are a diverse group of trans-membrane proteins that control cellular growth, survival and differentiation. Constitutive activation of RTKs is a hallmark of cancers, and can occur via copy number amplifications, point mutations, gene fusions or combinations of these events. Several RTKs are important anti-cancer targets that can be inhibited by small molecules and antibodies. Treatments with RTK inhibitors have had promising results in some cancers with RTK alterations (e.g., non-small cell lung cancer), but limited effectiveness in others (e.g., glioblastoma multiforme). This discrepancy warrants further study of the RTK pathway alterations in glioblastoma and across different cancer types.

Seventy-nine percent of TCGA glioblastoma multiforme (GBM) tumors with wild type IDH1 and IDH2 (IDHwt) harbor at least one somatic alteration in genes associated with the RTK signaling pathway. These include aberrations in RTKs themselves (EGFR, FGFR, MET, NTRK and PDGFR) or downstream components of their signaling (PI3K complex and PTEN). Of these, alterations in EGFR are most frequent and occur in over 45% of IDHwt GBM cases, including EGFR amplifications (32%), point mutations (4%), and combinations of amplifications and point mutations (15%). Our analysis of the TCGA lower-grade glioma (LGG) cohort revealed similar patterns of RTK signaling activation in 73% of IDHwt LGGs. In the IDHwt LGG cohort, EGFR amplifications occur in 11% of cases, point mutations in another 10% of cases, and multiple EGFR alterations in an additional 16% of cases.

Along with amplifications and point mutations, fusions of FGFR, EGFR and NTRK have been reported in IDHwt GBM and found to occur in IDHwt LGGs by our group. Based on this work, targeting RTKs other than EGFR has emerged as a potential treatment strategy for IDHwt gliomas. While activating RTK events in gliomas and other cancers are well known, their effect on downstream pathway signaling has not been fully elucidated. First, it is unclear whether the different mechanisms of RTK activation have similar effects on downstream pathway activity. Second, it is unknown how multiple types of RTK activation that occur in the same patient interact together to impact the signaling cascade. To address these questions, we used PARADIGM pathway analysis to estimate RTK pathway activity across 28 TCGA tumor types, including LGG and GBM. We then used PARADIGM-Shift to explore the effects of different types of RTK pathway alterations on the downstream signaling cascade. Our analysis implicates FGFR, NTRK and EGFR fusions as the strongest activators of RTK signaling in IDHwt gliomas. We also show that multiple RTK alterations in the same sample produce stronger pathway activation than single alterations. These experiments provide a framework for predicting sensitivity to RTK inhibitors across cancer types.

Citation Format: Olena Morozova, Sam Ng, Arjun Rao, Josh Stuart, David Haussler, Sofie Salama. Pan-cancer analysis reveals distinct effects of receptor tyrosine kinase mutations on downstream pathway activities. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-52.