Abstract A016: Positive ecological interaction between therapy-resistant and sensitive cells, mediated by stromal niche, slows the expansion of resistant subpopulations and promotes tumor heterogeneity

Abstract

Abstract Despite strong initial responses, advanced cancers inevitably develop resistance to pharmacological inhibitors of mutant tyrosine kinases, including EML4-ALK fusion, which drives neoplastic transformation in a subset of lung cancers. Whereas the main thrust of research and development efforts to tackle the issue of resistance is directed toward identification and targeting specific molecular mechanisms, there is also a growing interest in developing strategies to suppress the ability of neoplastic populations to evolve resistance. The success of these strategies is contingent on the accuracy of the basic assumptions on how resistance arises. One of the key issues is the uncertainty over whether the acquired resistance reflects an expansion of pre-existing fully resistant populations or develops de novo from weakly resistant cells initially capable of only narrowly avoiding elimination. To elucidate this question, we decided to examine the impact of a minor subpopulation of resistant cells on the evolutionary dynamics of therapy responses to ALK inhibitors. To this end, we used an integration of experimental studies in mouse xenograft models of ALK+ lung cancers with agent-based in silico modeling approaches. We found that therapy induces a rapid expansion of pre-existing subpopulations, leading to a quick transition toward relapse. Surprisingly, resistant cells modulated the dynamics of sensitive cells, preserving the survival and expansion of their sensitive competitors, indicating a positive ecological interaction. Spatial histological analyses revealed that this positive interaction was mediated by the preservation and expansion of stromal niches that both boosted the competitive fitness of therapy-sensitive cells and promoted their adaptation, thus facilitating tumor heterogeneity. Whereas this effect inhibited the competitive expansion of resistant cells and tumor relapse, our analyses suggest that pre-existing resistance is incompatible with long remissions observed in a large subset of patients treated with advanced ALK inhibitors. In summary, our results challenge a common assumption of the pre-existence of full resistance prior to therapy and highlight the essentiality of considering ecological factors in understanding the evolutionary dynamics of therapy responses. Citation Format: Bina Desai, Mark Robertson-Tessi, Robert Vander Velde, Tatiana Miti, Sagnik Yarlagadda, Rishi Shah, Daria Miroshnychenko, David Basanta, Alexander Anderson, Andriy Marusyk. Positive ecological interaction between therapy-resistant and sensitive cells, mediated by stromal niche, slows the expansion of resistant subpopulations and promotes tumor heterogeneity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A016.