While the use of targeted therapeutics for the treatment of cancer is certainly one of the most important strategies for treating this heterogeneous disease, progress has been hindered by an incomplete understanding of the survival circuitry which, when activated, can enable cancer cells to survive these therapies, leading to sub-optimal outcomes in patients. Mounting clinical and experimental evidence suggests that cancers co-opt survival through multiple pathways and that co- inhibition of these pathways can sensitize malignant cells to treatment. Thus, sensitizer therapies may represent a means to increase both the number of patients who initially respond to a given targeted therapy and the durability of that response. While combinatorial drugging strategies are an attractive and emerging treatment option, the full landscape of drug sensitizers across malignancies is not well understood. In this work, I propose to functionally map the pathways that determine sensitivity to targeted therapies for genotypically distinct cancers using a targeted library of CRISPR reagents in a miniaturized pooled-screening approach. Ours will be the first attempt to functionally examine these relationships and, if successful, will provide rational therapeutic strategies for improving treatment efficacy as well as informing on cancer cell survival networks.
Our work seeks to address a critical question in cancer biology: what allows a cancer cell to survive and persist in the presence of a molecularly targeted therapy? Here, we propose to use new, systematic methods to define the molecular pathways that act in concert to promote cancer cell survival during drug treatment in a variety of cancer contexts, and then use this information to design combination therapies that enhance treatment efficacy. These studies promise to improve our understanding of compensatory survival signaling in cancer cells and lead to new therapeutic strategies to improve outcomes in patients.
| Anderson, Grace R; Winter, Peter S; Lin, Kevin H et al. (2017) A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution. Cell Rep 20:999-1015 |
| Lin, Kevin H; Winter, Peter S; Xie, Abigail et al. (2016) Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia. Sci Rep 6:27696 |
