Research

Dana-Farber Researchers Map the Degradable Kinome, Providing Chemical Leads for Over 200 Kinases

In a new paper published in Cell, Dana-Farber investigators described chemo-proteomic approaches to identify kinases that are amenable to targeted protein degradation (TPD). Eric Fischer, PhD, and colleagues used a panel of cell lines expressing nearly 500 protein kinases, and treated them with a library of 89 unique kinase degraders, which collectively bind the majority of the kinome. Using mass spectrometry, they identified which kinases are chemically degraded, and identified nearly 200 highly-degradable kinases and documented their findings in a searchable online database for researchers ...

Investigating PARP Inhibitor Resistance in BRCA1-Associated Triple Negative Breast Cancer

Recent clinical trials on BRCA1-associated triple negative breast cancer (TNBC) have investigated pairing PARP inhibitor therapy with immunotherapy. However, response rates have only shown modest improvements. Led by Jennifer Guerriero, PhD, a team of DF/BWCC researchers investigated and reported in Nature Cancer what else in the tumor microenvironment is limiting the efficacy of this combination. Through multi-omics profiling, PARP inhibitors were shown to increase intratumoral macrophages and modulated the metabolic phenotype, driven by the sterol regulatory element-binding protein 1 (SREBF1, SREBP1) pathway ...

Paralog Enzymes VPS4A and VPS4B in Cancers Link to Genetic Vulnerability

Andrew Aguirre, MD, PhD, in collaboration with the Cancer Dependency Map (DepMap) project at Dana-Farber and the Broad Institute of MIT and Harvard, reports in Cell Reports a genetic dependency that could be present in more than 30% of all cancers. In this study led by co-first authors Brenton Paolella, PhD, and Jasper Neggers, PhD, of the Aguirre Lab, large-scale CRISPR-SpCas9 and RNA interference (RNAi) loss-of-function screening of more than 600 cancer cell lines was implemented to systematically define synthetic lethal vulnerabilities associated with genomic loss of established tumor suppression genes ... 

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