LAUSR

Our laboratory uses genomic and pharmacological methods to define the pathways of resistance to targeted anticancer therapies. Toward this end, we recently developed a technique in which engineered lentiviral cDNAs encoding activators of major oncogenic signaling pathways are introduced into cells and then profiled to identify those capable of conferring resistance to drugs. In parallel, we have also developed analogous loss-of-function screening approaches based on CRISPR/Cas9 gene editing, and have used these approaches to map the pathways supporting intrinsic resistance to targeted therapies. Using these tools in conjunction with data and mouse models derived from human tumors, we recently discovered that major pathways of resistance frequently converge onto common downstream effectors, the targeting of which can forestall resistance. Here, I will describe the discovery of common resistance effectors in JAK2-driven myeloproliferative neoplasms, EGFR-driven colorectal cancers, and BRAF-driven melanomas. Focusing particularly on melanoma, I will describe the discovery that major pathways of resistance converge to activate the transcription factor c-MYC (MYC). MYC expression and gene signatures were suppressed following initial drug treatment, then rebounded during tumor progression in each member of a large panel of human patients, independent of the upstream pathway driving resistance. MYC suppression using either genetic approaches or BET bromodomain inhibition was sufficient to both resensitize diverse BRAFi/MEKi-resistant models and delay resistance in treatment naive models. Although direct pharmacological inhibition of MYC remains difficult, the BRAFi/MEKi-resistant, MYC-activated state harbors synthetic lethal signaling and metabolic dependencies, including those involving SRC family and c-KIT tyrosine kinases and glucose, glutamine, and serine pathways, that can be targeted to create combination therapies that uniquely select against resistance evolution. Citation Format: Kris C. Wood. Leveraging synthetic lethality to target convergent therapeutic resistance [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr PR18.