Abstract 71: Integrated-omics analysis identifies the druggable achilles targets to sensitize cancer cells with gefitinib resistance

• Published in: Cancer research (Chicago, Ill.) Vol. 82; no. 12_Supplement; p. 71
• Main Authors: Kwon, Eun-Ji, Lee, Haeseung, Cha, Hyuk-Jin
• Format: Journal Article
• Language: English
• Published: 15.06.2022
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2022-71

Abstract Limited eligibility remains one of major drawbacks of target therapeutics as the oncogenic dependency is only determined by mutation status of a target. In order to extend the eligibility of target therapeutics, transcriptome profiles of patients have been examined to better delineate sensitivity of target therapeutics. In this study, we took advantage of multiple large datasets such as cancer cell line transcriptome data (CCLE), drug response data (CTRP), and gene dependency data (Achilles Project) to determine the sensitivity markers of tyrosine kinase inhibitors currently approved by FDA. In particular, EGFR inhibitors (iEGFR: lapatinib, gefitinib and erlotinib) revealed clear sensitivity cluster of cell line regardless of EGFR mutation status. Comparative analysis between sensitive (iEGFR-S) and resistant (iEGFR-R) cell groups revealed that integrated gene signatures such as chemokine, GPCR, and PI3K-Akt signaling pathway, were predicted as putative determinants of iEGFR susceptibility. Through integrated analysis of gene dependency data, among several Achilles’ targets (of which depletion increases vulnerability), predicted in iEGFR-R cells group, druggable Achilles’ targets (available to accompanied drugs) such as CCR6, AURKA and mTOR were identified as putative targets for sensitizing iEGFR-R group to iEGFR. Following biochemical studies validated the clear sensitizing effect of the pharmacological inhibitor for each predicted target, in the isogenic cell models with acquired iEGFR resistance. In addition, prediction and following biochemical validation, we demonstrated that the CCR6 inhibition significantly attenuated resistance of iEGFR by repressing mitochondrial ROS (mt-ROS), of which induction by iEGFR rescued cell death. These data suggest that integrated-omics analysis would be a useful approach to extend eligibility and improve the efficacy of target therapeutics. Citation Format: Eun-Ji Kwon, Haeseung Lee, Hyuk-Jin Cha. Integrated-omics analysis identifies the druggable achilles targets to sensitize cancer cells with gefitinib resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 71.