Abstract B24: Differential sensitivity to Aurora kinase inhibition in RIT1- and KRAS-mutant lung adenocarcinoma

Abstract

Mutations in Ras-family genes Kirsten rat sarcoma viral oncogene (KRAS) and Ras-like in all tissues (RIT1) occur in 30% and 2% of lung adenocarcinomas, respectively. Targeted therapies have shown promise in lung adenocarcinomas and other cancers; however, there are currently no FDA-approved drugs that directly target RIT1 or KRAS. To identify critical effector pathways and/or genetic dependencies that might be targeted for clinical benefit in these cancers, we undertook complementary proteomic and small-molecule screens in multiple human lung cancer models. To better understand the signaling networks modulated by RIT1 and KRAS, we performed deep characterization of total protein and phosphoproteins in non-transformed human lung epithelial cells engineered to express mutant or wild-type RIT1 or KRAS. 10,131 proteins were detected across all samples, 9,001 of which were detected in every sample. 29,172 phosphorylated sites were detected with 14,769 of these identified in every sample. Gene set enrichment analysis (GSEA) identified pathways significantly modulated by RIT1 M90I, KRAS G12V, or KRAS Q61H mutations. Whereas some pathways, such as MYC, were commonly activated by both mutant RIT1 and KRAS, others, such as Aurora kinase signaling, were specifically perturbed by RIT1. Previously, we found that mutant RIT1 and KRAS can transform human lung epithelial cells and confer resistance to EGFR blockade in EGFR-dependent lung adenocarcinoma. To identify opportunities for therapeutic intervention of RIT1- and KRAS-mutant tumors, we screened a collection of 160 small molecules for their ability to block RIT1/KRAS-induced drug resistance in PC9 cells, an EGFR-mutant lung adenocarcinoma cell line. Interestingly, RIT1 M90I-expressing cells were selectively killed as a result of treatment with the Aurora kinase inhibitors, alisertib and barasertib, while KRAS G12V cells were resistant to these inhibitors. The specific effect of Aurora kinase inhibition on RIT1 mutant cells was also confirmed in a fibroblast transformation assay and could not be attributed to proliferation rate, which was similar between RIT1- and KRAS-expressing cells. Moreover, Aurora kinase B (AURKB) was among the most differentially expressed transcripts when comparing RIT1- or KRAS-expressing cells, suggesting differential effects of RIT1 and KRAS on Aurora kinase activity. These findings nominate Aurora kinase inhibition as a potential therapeutic strategy in RIT1- , but not KRAS-mutant, lung cancer. Citation Format: Kristin D. Holmes, Filip Mundt, Phillip Mertins, Steve Carr, Alice Berger. Differential sensitivity to Aurora kinase inhibition in RIT1- and KRAS-mutant lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B24.