Targeted therapies and immunotherapies are two of the most transformative and promising advances in cancer treatment over the last two decades. Yet they, like conventional chemotherapies, frequently succumb to the ability of cancers eventually to resist therapeutic attacks on their vulnerabilities, reversing the initially impressive clinical responses to these treatments. This project focuses on conserved non-mutational mechanisms of resistance that are frequently encountered in resistance arising in multiple therapeutic regimens across multiple cancer types. In the current phase of the CTD2 Network, we developed powerful new tools and capabilities that enable the community to identify novel cancer vulnerabilities. The method relies on the Cancer Therapeutics Response Portal (CTRP), which houses a large dataset of quantitative compound sensitivity data and has been made available without restriction. Using CTRP, we found evidence for the existence of at least one such common therapy-resistant state, associated with mesenchymal characteristics of cancer cells. Importantly, this state emerges from treatment with either chemotherapy or targeted therapeutics across several cancer types. This project aims to fully dissect this pathway, and to discover other such pathways, to understand the bases of resistant-state vulnerabilities, and to learn how to exploit them therapeutically in a safe and effective way.
Overcoming resistance to cancer therapy has emerged as one of the most pressing and universal issues in oncology. We have developed powerful new tools and capabilities that enable the community to identify novel cancer vulnerabilities, including those that arise in cancer resistance. This project aims to 1) discover common drug-resistant cancer cell states, 2) define vulnerabilities of these cancer cell states, and 3) identify small molecules that can attack those vulnerabilities, providing a path forward for combination therapies aimed at curing cancers.
|Liu, Hengrui; Schreiber, Stuart L; Stockwell, Brent R (2018) Targeting Dependency on the GPX4 Lipid Peroxide Repair Pathway for Cancer Therapy. Biochemistry 57:2059-2060|
|Basu, Amrita; Mitra, Ritwik; Liu, Han et al. (2018) RWEN: response-weighted elastic net for prediction of chemosensitivity of cancer cell lines. Bioinformatics 34:3332-3339|
|Aksoy, Bülent Arman; Dancík, Vlado; Smith, Kenneth et al. (2017) CTD2 Dashboard: a searchable web interface to connect validated results from the Cancer Target Discovery and Development Network. Database (Oxford) 2017:|
|Viswanathan, Vasanthi S; Ryan, Matthew J; Dhruv, Harshil D et al. (2017) Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547:453-457|
|Speyer, Gil; Mahendra, Divya; Tran, Hai J et al. (2017) DIFFERENTIAL PATHWAY DEPENDENCY DISCOVERY ASSOCIATED WITH DRUG RESPONSE ACROSS CANCER CELL LINES. Pac Symp Biocomput 22:497-508|
|Hangauer, Matthew J; Viswanathan, Vasanthi S; Ryan, Matthew J et al. (2017) Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551:247-250|
|Lewis, Timothy A; Sykes, David B; Law, Jason M et al. (2016) Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia. ACS Med Chem Lett 7:1112-1117|