Abstract IA016: Resistance to ALK-targeting therapies in lung cancers is acquired through complex, context specific evolutionary trajectories
Authors: Marusyk Andriy 
Published: May 2022

Abstract
Background. Despite remarkable initial efficacy, targeted therapies eventually fail in advanced lung cancers. This failure reflects the ability of neoplastic populations to adapt to therapy-imposed selection pressures. In principle, disrupting this ability might transform clinical outcomes. However, contrast to the detailed understanding of individual molecular mechanisms of resistance, our knowledge of how neoplastic populations adapt remains limited. Based on inferences from mechanistic studies, it is commonly assumed that adaptation results from the acquisition of a single mutational change, or an epigenetic switch-like phenotypic state transition. Findings. Using a combination of experimental studies and in silico modeling, we sought to dissect evolutionary trajectories towards acquired resistance to clinically relevant ALK inhibitors in experimental models of ALK+ NSCLC. Consistent with the growing appreciation of the phenomenon of therapy persistence, we found that near-complete resistance originates from weakly resistant populations. Surprisingly, these populations were phenotypically heterogeneous and differed between different ALKi. Rather than the frequently assumed saltational transition from persistence to resistance, we observed a gradual loss of therapy sensitivity, mediated by acquisition of multiple epigenetic and mutational resistance mechanisms. This multifactorial progression was observed even in the presence of mutational drivers that are ostensibly sufficient to explain clinical resistance. Interestingly, even though resistance to any of the ALKi was linked with cross-resistance to other ALKi, we observed a clear divergence of evolutionary trajectories under selection with distinct inhibitors. In contrast, independent resistant derivates selected with same inhibitor displayed remarkable convergence, where similar phenotypic states were achieved through distinct mechanistic changes. Notably, evolving cells displayed inhibitor-specific, temporally restricted collateral sensitivities, suggesting new opportunities for therapeutic interference. Whereas, in vitro, evolving resistance was primarily shaped by cell-intrinsic mechanisms, acquisition of resistance in vivo reflected an interplay between cell-intrinsic mechanisms and stromal sheltering niches. Conclusions. Therapy resistance can be acquired through complex, context and inhibitor specific evolutionary trajectories that integrate mutational and epigenetic changes as well as modifying effect of macro and micro-environments. Consequently, even in the presence of strong mutational drivers, focusing on a single resistance mechanism at a time is unlikely to produce substantial therapeutic breakthroughs. Our results suggest a need for multifactorial therapeutic interventions that disrupt the ability of tumors to adapt to therapies.
Citation Format: Andriy Marusyk. Resistance to ALK-targeting therapies in lung cancers is acquired through complex, context specific evolutionary trajectories [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 IA016.