Using genetic data from around 10,000 patients, Julian Hess, associate member Michael Lawrence, institute member Gad Getz (all in the Cancer Program), and their colleagues have developed a model that accurately separates cancer driver hotspot mutations from passenger ones. Using their model, they found that many mutations in hotspots in the genome are in fact passengers rather than drivers as previously thought. The model was rigorously vetted to show that it doesn’t generate the false positives that have plagued older models. Read more in Cancer Cell and in a Broad news story.
How to energize tired T cells
In cancer and chronic viral infections, CD8+ T cells become exhausted — they lose their ability to proliferate and to kill tumor and infected cells. Institute member Arlene Sharpe, associate member W. Nicholas Haining, and their collaborators have found a possible way to boost the cell-killing abilities of some of these tired cells. They identified a phosphatase, PTPN2, that regulates the generation of the exhausted Tim-3+ subpopulation. Deleting the Ptpn2 gene in CD8+ T cells increased their number, cytotoxicity, and anti-tumor responses. The team concludes that PTPN2 in immune cells is a promising drug target for cancer immunotherapy. Read more in Nature Immunology.
Roots of CLL resistance and relapse revealed
Targeted inhibitors like venetoclax have changed the treatment landscape for B cell cancers, but many patients relapse. Romain Guièze and institue member Catherine Wu in the Cancer Program worked with colleagues at Dana-Farber Cancer Institute and in the Broad’s Proteomics Platform, Metabolism Program, and Genetic Perturbation Platform to identify the roots of venetoclax resistance in chronic lymphocytic leukemia. Reporting in Cancer Cell, they found that cells that can evade venetoclax treatment show overexpression of MCL-1 and altered cellular energy metabolism, suggesting that combination therapies could treat B cell cancers while avoiding resistance.