crc-23-0482_fig2.png (680.63 kB)

FIGURE 2 from Synergy of EGFR and AURKA Inhibitors in KRAS-mutated Non–small Cell Lung Cancers

figure

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

Sensitivity of NSCLC cell lines to erlotinib and alisertib. A, Western blot images and quantification of the protein levels of EGFR and AURKA in NSCLC cell lines and the human fibroblast cell line FC1010. Data for NSCLC cell lines are normalized to the levels in FC1010 cells. B, Determination of AURKA gene copy number in NSCLC cell lines, using the colorectal cancer cell lines HCT116 and SW420 as standards. Normalization to RNAseP, blue, or ALB, orange. The slopes of the standard curves were −3.64 (AURKA), −3,46 (RNAseP), −3.49 (ALB). Determination of sensitivity of the NSCLC cell lines and FC1010 control to erlotinib (C) and alisertib (D), with quantified IC₅₀ values (E), based on CelltiterBlue analysis of viability after growth with indicated drugs for 72 hours. N/A, IC₅₀s were not calculated because of low sensitivity to the drug. F, Combination indexes for erlotinib and alisertib over a range of molar ratios. Results shown reflect averages from four to five independent experiments, each done in quadruplicate, ± SEM and were calculated using CompuSyn software.

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.