Abstract 2233: Landscape of driver mutations in MAPK/PI3K/AKT signaling pathways reveals insights into therapeutic targeting strategies
Authors: Sivakumar Smruthy , Sokol Ethan S. , Frampton Garrett M. , Hegde Priti S. , Fabrizio David 
Published: July 2021

Alterations in the signaling cascade of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways are common mechanisms of cancer initiation and progression. RAS proteins (KRAS/HRAS/NRAS), a crucial component of this cascade, are often found to be activated in cancer cells. Recent advancements in RAS targeting offer new treatment strategies for patients, however studies suggest that the clinical responses may be tissue-dependent. Thus, understanding the landscape of RAS alterations and the concomitant mutations observed in their effector pathways may be crucial in developing appropriate disease-specific therapeutic strategies for effectively addressing this biology.

In this study, we utilized comprehensive genomic profiling data from 282,792 cancer patients across 77 tumor types, tested in the course of routine clinical care (FoundationOne) to assess the landscape of gene alterations within this signaling cascade. RAS alterations were identified in 27% of the cohort. Mutations in PI3K and PTEN were also frequent (&gt;10%); alterations in FGFR1-4, EGFR, RAF (ARAF/BRAF/RAF1) and ERBB2 were each identified in over 5% of samples. A closer inspection of non-small cell lung carcinomas (NSCLC, n=55,893), colorectal carcinomas (CRC, n=35,104) and pancreatic cancers (PC, n=17,447), revealed distinct mutational spectrums. RAS alterations, particularly KRAS, exhibited varying prevalence: PC (85%), CRC (54%) and NSCLC (32%). In NSCLC, 35% of the KRAS alterations were identified to be G12C. In contrast, the predominant KRAS alterations in CRC and PC were G12D (29% CRC, 41% PC) and G12V (20% CRC, 30% PC). Further, only CRCs exhibited a high rate of KRAS G13D (16% of all KRAS alterations); KRAS G12R was found exclusively to PC (15%) and KRAS amplifications were most frequently identified in NSCLC (11%). Distinct patterns were also observed in genes upstream and downstream of the RAS proteins. Alterations in ALK, EGFR, STK11 and MET were significantly more prevalent in NSCLC (P &lt; 10−5); whereas gene alterations in PI3K, RAF, MTOR and ERBB2 were more frequently identified in CRC (P &lt; 10−5). In contrast, PC showed a predominant presence of RAS mutations, with limited mutations in other genes of the signaling cascade. Of note, PI3K alterations were identified at a much lower prevalence in PC (4%) compared to NSCLC (11%) and CRC (19%).

Our findings suggest a tissue-dependent spectrum of driver mutations exist across the MAPK/PI3K/AKT signaling pathways. The observed mutational profiles may explain some of the efficacy differences observed by targeting RAS across these diseases and have implications on acquired resistance mechanisms in a tissue-specific manner. Additional insights may be gleaned by investigating immunotherapy related biomarkers with these alterations to suggest combination strategies for effectively targeting the RAS signaling cascade.

Citation Format: Smruthy Sivakumar, Ethan S. Sokol, Garrett M. Frampton, Priti S. Hegde, David Fabrizio. Landscape of driver mutations in MAPK/PI3K/AKT signaling pathways reveals insights into therapeutic targeting strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2233.