Research Roundup: October 4, 2019

A multipronged effort to understand leukemia resistance, building a better phage, mapping MS genetics, and more.

Erik Jacobs
Credit: Erik Jacobs

Welcome to the October 4, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Digging for the roots of cancer drug resistance 

In a Broad news story, researchers from several Broad programs and platforms describe their remarkable collaboration with institute member Catherine Wu and her lab in the Cancer Program to explore how leukemia cells outwit a targeted cancer drug. With help from Guo Wei, Cory Johannessen, and institute member Gad Getz in the Cancer Program; Federica Piccioni and institute scientist John Doench in the Genetic Perturbation Platform, Namrata Udeshi and institute scientist Steven Carr in the Proteomics Platform, and Alexis Jourdain and institute member Vamsi Mootha in the Metabolism Program, the Wu lab brought the power of the Broad environment to bear, revealing that resistant cells reprogram cellular metabolism to survive treatment. Learn more about their findings in Cancer Cell.

Turning a new phage

The rise of antibiotic resistance has kindled interest in using bacteria-infecting viruses, called phages, as antimicrobial agents. However, bacteria also evolve resistance to phages, so new strategies are required for enhancing phage efficacy. Drawing inspiration from antibody engineering techniques, Kevin Yehl, Cell Circuits Program associate member Timothy Lu, and colleagues developed a high-throughput approach for making specific mutations in phages’ tail fiber protein to produce enhanced phages, dubbed “phagebodies,” that can infect resistant bacteria. The method produces phagebodies that potently clear bacterial infections in an animal model, without signs of resistance, and can scale modified phage production up into the millions. Read their full report in Cell.

A SHOC-ing vulnerability in RAS-driven cancers

Cancer drugs that inhibit a protein called MEK (part of the MAPK pathway) haven’t worked well for patients with RAS mutations. Rita Sulahian, Jason Kwon, institute member William Hahn, and associate member Andrew Aguirre of the Cancer Program, Katherine Walsh of the Center for the Development of Therapeutics, and colleagues looked for genetic vulnerabilities in RAS-driven cancer cells that other drugs could target in combination with MEK inhibitors. The researchers conducted CRISPR-Cas9 screens in KRAS-mutant pancreatic and lung cancer cell lines in the presence of MEK inhibition, and identified several synthetic lethal vulnerabilities, including members of the MAPK pathways. The strongest and most common synthetic lethal target with MEK inhibition was SHOC2, which the authors say is a potential target for combination therapy for RAS-driven cancers. Read more in Cell Reports.

Building the genetic map of MS

Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system that predominantly strikes young adults. In Science, Program in Medical and Population Genetics associate member Nikolaos Patsopoulos, Columbia University's Philip De Jager, numerous Broad scientists, and their colleagues in the International Multiple Sclerosis Genetics Consortium, now report a detailed genomic map of MS from 47,429 MS patients and 68,374 healthy individuals. The results implicate many different immune cell types in MS, and the authors say these insights will set the stage for a new generation of functional studies to understand how the disease is triggered.

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