Abstract 2118: Collateral resistance trajectories following failure to antimitotic drugs

Abstract

Abstract Secondary drug resistance stems from dynamic clonal evolution during the development of a prior primary resistance. This collateral type of resistance is often a characteristic of cancer recurrence. Yet, mechanisms that drive this collateral resistance and their drug-specific trajectories are still poorly understood. Using resistance selection in concert with small-scale pharmacological screens and data mining in a large pharmacogenomics database, we identified and validated unique collateral resistance trajectories that occur between chemically-different classes of drugs. One convincing case is the co-resistance between microtubule-targeting drugs and EGFR-tyrosine kinase inhibitors (EGFR-TKIs). With paclitaxel resistance as a proxy first-line drug failure model and EGFR-TKI resistance as a collateral, we find that a prior resistance can follow distinct trajectories towards collateral resistance, leading to formation of more stable resistant cell populations. These trajectories can be directed by mechanisms regulating the entry to a drug-tolerant persistent state during exposure to therapy. Collectively, our work unravels the alterations in cellular states defining collateral resistance trajectories to EGFR-TKIs following prior resistance to antimitotic drugs. Note: This abstract was not presented at the meeting. Citation Format: Mark Borris D. Aldonza. Collateral resistance trajectories following failure to antimitotic drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2118.