Abstract B016: Selection and reprogramming contribute to the evolution of targeted therapy resistance

Abstract

Targeted therapies provide substantial benefits to cancer patients by shrinking and controlling tumors. However, the long-term efficacy of targeted therapy is limited by the development of resistance. Once a tumor is fully resistant, it continues to grow despite the presence of the targeted therapy, leading to disease relapse in the patient. When the therapy is first applied, a number of studies have now shown that there is initially a selection for cells that are able to tolerate the drug (termed “tolerant cells”). This contrasts with selection of fully resistant cells. More recently our studies have suggested that the transition from tolerance to resistance is not binary and involves multiple changes. These changes can be propelled by the stochastic generation of heritable heterogeneity followed by selection (Darwinian evolution), by long-term changes in signaling networks (reprogramming) and by combinations of these two. The contribution of these factors determines the usefulness of strategies using either evolutionary dynamics (such as reducing population size or changing selective pressures on tumor cells) or therapies that alter cell states (such as inhibiting or activating key signaling nodes). We are using colony assays and developing barcoding techniques to address the role of selection and clonality in the evolution of full resistance to BRAF inhibitors in melanoma from a tolerant state. Early results show a rapid increase in fitness (relative to surviving tolerant cells) suggesting a role for selection immediately after the first selective event. These changes are followed by slow changes that may be the result of mostly reprogramming. This implies that strategies that manipulate evolutionary dynamics are most effective early in resistance evolution while later changes can be manipulated by altering signaling nodes. Citation Format: Robert Vander Velde, Sydney Shaffer. Selection and reprogramming contribute to the evolution of targeted therapy resistance [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B016.