Abstract 3469: Dual inhibition of the EGFR and Aurora A pathways in Kras mutated non-small cell lung cancers

Abstract

Abstract Lung cancer is the leading cause of cancer related death in the US. Patients with advanced disease generally have a poor prognosis with a median survival of around 10 to 12 months with standard chemotherapy. In patients with non-squamous non-small cell lung cancers (NSCLC) incidence of KRAS mutations reach ~22%. Specific treatments for Kras mutated NSCLC have not been developed although recent reports suggest an advantage for treatment with immunotherapy over chemotherapy in the second line setting. Published reports using a synthetic lethal screening method show that the combined inhibition of the EGFR and Aurora A kinase pathways could have synergistic effect on viability in head and neck and colon cancer cell lines suggesting a potential benefit of such combination therapy in these patients (Astsaturov and colleagues, 2010). Our study aims to examine the effects of combination of erlotinib (E), an EGFR small-molecule inhibitor, and Alisertib (MLN8237, A), an inhibitor of Aurora A kinase, in lung cancer models with different KRAS status. Human NSCLC cell lines with both wild type and mutated KRAS showed weak or moderate sensitivity to both drugs in vitro. Treatment with both E and A had synergistic activity in all examined cell lines, wild type KRAS (H2228, H1299) or mutated KRAS (A549, H1299, H358, H460, and H62). Western blot analysis confirmed that combination treatment enhanced apoptosis compared to single drug use as evidenced by cleaved PARP. In xenograft models, CB17 SCID mice were treated with single drug or E+A for three weeks. H322M xenograft tumors bearing wild type KRAS were moderately sensitive to growth inhibition by E (10 mg/kg/day) and A (20 mg/kg/twice daily) alone and the combination had an additive effect. A549 and H358 xenografts were insensitive to E because of the mutated KRAS and moderately sensitive to A. However, the combination of E+A had a synergistic effect and significantly inhibited tumor growth. Western blot analysis of signaling pathways downstream of the EGFR and Aurora A in tumor xenografts shows synergistic inhibition after two-drug treatment. Our results suggest that combined inhibition of both pathways might be an effective treatment strategy for lung cancers harboring KRAS mutations. Citation Format: Tetyana Bagnyukova, Brian Egleston, Mackenzie Kramer, Igor Astsaturov, Erica Golemis, Hossein Borghaei. Dual inhibition of the EGFR and Aurora A pathways in Kras mutated non-small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3469.