IA17 Druggable Vulnerabilities in Therapy-Resistant Lung Cancers

Abstract

Oncogene-targeted therapies often drive therapeutic responses in patients with advanced lung cancers, but frequently these responses eventually give way to acquired resistance. Blocking acquired resistance is a substantial and open-ended challenge whose difficultly is underscored by the fact that resistance within individual patients is often polyclonal in nature, driven by diverse and co-occurring mechanisms. Here, I will discuss two broad approaches we are employing in the search for therapeutic strategies that delay or circumvent resistance evolution. In the first area, we have identified vulnerabilities present in tumors at minimal residual disease states. For example, we have identified a molecular pathway through which targeted therapies such as EGFR, ALK, and BRAF inhibitors trigger double-strand DNA breaks in the cancer cells that comprise the minimal residual disease state. These cells rely upon an ATM-dependent DNA repair process for their survival and are thus hypersensitive to ATM inhibition. As such, combining oncogene-targeted therapies with an ATM inhibitor leads to more penetrant and durable responses to these agents in vivo. In the second area, we have identified vulnerabilities that arise specifically in tumor cells that develop acquired resistance to oncogene-targeted therapies. Importantly, we have identified scenarios in which these “collateral sensitivities” are conserved across heterogeneous resistant clones with distinct resistance mechanisms, implying that targeting these mechanisms may simultaneously eradicate diverse clones. I will describe examples of mechanism-based collateral sensitivities we have uncovered in lung cancers, melanomas, and leukemias, then demonstrate that by targeting these mechanisms in the upfront setting, it is possible to construct combination therapies that select against resistance.