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posted on 2024-05-08, 14:20 authored by Tetyana Bagnyukova, Brian L. Egleston, Valerii A. Pavlov, Ilya G. Serebriiskii, Erica A. Golemis, Hossein Borghaei Signaling patterns in KRASmut NSCLC xenografts 6 or 24 hours after treatment with erlotinib or/and alisertib. Quantification of Western blot images for A549 (A) xenograft tumors. Data are presented as mean ± SEM, n = 3–6 mice. B, Summary for A549 xenografts shows significant changes in protein levels and activation after erlotinib+alisertib treatment, in reference to vehicle treated control group. C, Quantification of Western blots for H358 xenograft tumors. Primary Western blot data are shown in Supplementary Figs. S4 and S5. *, Significantly different from corresponding groups with P < 0.05; **, P < 0.01; or ***, P < 0.001. Color of asterisks indicates comparison groups as follows: red, to control; orange, combination to erlotinib; green, combination to alisertib, purple, alisertib to erlotinib. C, vehicle; E, erlotinib; A, alisertib; EA, erlotinib + alisertib.
Funding
HHS | NIH | National Cancer Institute (NCI)
William Wikoff Smith Charitable Trust
History
ARTICLE ABSTRACT
The most common oncogenic driver mutations for non–small cell lung cancer (NSCLC) activate EGFR or KRAS. Clinical trials exploring treatments for EGFR- or KRAS-mutated (EGFRmut or KRASmut) cancers have focused on small-molecule inhibitors targeting the driver mutations. Typically, these inhibitors perform more effectively based on combination with either chemotherapies, or other targeted therapies. For EGFRmut NSCLC, a combination of inhibitors of EGFR and Aurora-A kinase (AURKA), an oncogene commonly overexpressed in solid tumors, has shown promising activity in clinical trials. Interestingly, a number of recent studies have indicated that EGFR activity supports overall viability of tumors lacking EGFR mutations, and AURKA expression is abundant in KRASmut cell lines. In this study, we have evaluated dual inhibition of EGFR and AURKA in KRASmut NSCLC models. These data demonstrate synergy between the EGFR inhibitor erlotinib and the AURKA inhibitor alisertib in reducing cell viability and clonogenic capacity in vitro, associated with reduced activity of EGFR pathway effectors, accumulation of enhanced aneuploid cell populations, and elevated cell death. Importantly, the erlotinib-alisertib combination also synergistically reduces xenograft growth in vivo. Analysis of signaling pathways demonstrated that the combination of erlotinib and alisertib was more effective than single-agent treatments at reducing activity of EGFR and pathway effectors following either brief or extended administration of the drugs. In sum, this study indicates value of inhibiting EGFR in KRASmut NSCLC, and suggests the specific value of dual inhibition of AURKA and EGFR in these tumors.
The introduction of specific KRAS G12C inhibitors to the clinical practice in lung cancer has opened up opportunities that did not exist before. However, G12C alterations are only a subtype of all KRAS mutations observed. Given the high expression of AURKA in KRASmut NSCLC, our study could point to a potential therapeutic option for this subgroup of patients.
