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Mary Ellen Hackett 

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Email maryellen.hackett@nih.gov or call 301-401-8670 for all media related questions.

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RTKs activate SHP2, which stimulates SOS to activate RAS through the exchange of GDP to GTP. KRAS G12C inhibitors target inactive, GDP-bound KRAS, and are antagonized by SOS activity. The addition of SHP2is leads to a higher accumulation of GDP-bound KRAS G12C and more efficient target engagement by KRAS G12Cis.

SHP2 Inhibitors for Treating Cancer

Chemotherapy resistance is a major roadblock in treating cancer. Discover how pairing SHP2 inhibitors with mutant-selective KRAS inhibitors is a promising strategy to outsmart adaptive resistance.POSTED: 4/15/2021
Graphic representation of RAS gene

Update: Mutations in Human Cancers Through the Lens of KRAS

 Authors' correction: An alert reader notified us that the data in the Broad Institute's Genome Data Analysis Center shows that EGFR genes in lung adenocarcinomas are indeed highly mutated only when KRAS is wild type (0/66, mutant/wild type). Our script failed to return this bias due to a #DIV/0! error. The text below, Figure 2A, and the Spreadsheet have now been corrected. In 2015 we published a RAS Dialogue that used TCGA ( The Cancer Genome Atlas) data to analyze the kinds of KRAS mutations found in cancers, and the genes that were frequently co-mutated (mutated along with KRAS), frequently contra-mutated (mutated when KRAS was wild type), or frequently mutated independent of KRAS status. Our data were downloaded from the Broad Institute’s GDAC (Genome Data Analysis Center), and comprised 122 pancreas (PAAD, pancreatic ductal adenocarcinoma), 226 lung (LUAD, lung adenocarcinoma), 149 colon (COAD, colon adenocarcinoma), and 217 rectal (READ, rectum POSTED: 1/30/2021
Headshots of Alba Luengo, Zhaoqi Li, and Matthew Vander Heiden

New Clarity on the Warburg Effect

 This research was performed at the Koch Institute for Integrative Cancer Research at MIT, where Matt Vander Heiden is Associate Director. Alba Luengo is now at Toran Therapeutics of the Flagship Pioneering Group, and Zhaoqi Li is a postdoc in the Department of Microbiology, Harvard Medical School. Nearly a century ago, Otto Warburg discovered that tumors consume tremendous amounts of glucose relative to most non-transformed tissues, and that the majority of glucose consumed by tumors is fermented to lactate, rather than oxidized in pathways that require respiration [1]. This phenotype is referred to as “aerobic glycolysis,” because unlike carbohydrate fermentation in response to oxygen limitation, aerobic glycolysis involves high levels of fermentation even when oxygen is abundant. Aerobic glycolysis a hallmark of proliferative metabolism found across many kingdoms of life, but is frequently associated with cancer cells, and is known as the Warburg effect in this context. What drives aerobic POSTED: 1/13/2021
Headshot of Dominic Esposito Ph.D

Deploying a RAS pipeline against the SARS-CoV-2 pandemic

 Dom Esposito earned his Ph.D. in Biochemistry and Biophysics at Johns Hopkins University and did postdoctoral work in the Laboratory of Molecular Biology at the National Institute of Diabetes and Digestive and Kidney Diseases. He helped develop the Gateway recombinational cloning system at Life Technologies, Inc., and has directed the Protein Expression Laboratory of the NCI’s Frederick National Lab since 2011. His management responsibilities include the RAS Reagents Core of the RAS Initiative, which provides DNA cloning, protein expression and purification, and qualified cell lines to the NCI RAS Initiative. Late on the evening of March 18, 2020, I was working on contingency plans for staffing the RAS Reagents Core (RRC) during the SARS-CoV-2 pandemic, when the first indication that we would become involved in studying the pandemic arrived. It came in the form of an email with the subject line “Help”. The sender was Dr. Matt Hall, a collaborator POSTED: 7/30/2020
Rob Kortum, MD, PhD, and Erin Sheffels, PhD

SOS signaling in RAS-mutated cancers

 Rob Kortum earned his Ph.D. with Rob Lewis at the University of Nebraska Medical Center, and trained with both Larry Samelson and Deborah Morrison at NCI. He is an assistant professor of Pharmacology at Uniformed Services University in Bethesda, MD. Erin Sheffels trained with Dr. Kortum and earned her Ph.D. in May 2020. She plans to do her postdoctoral work with Gina Razidlo at Mayo Clinic. RAS-mutated tumors were originally thought to proliferate independently of upstream signaling inputs, but we now know that receptor tyrosine kinase-dependent activation of both mutant RAS and non-mutated wild-type (WT) RAS plays an important role in modulating downstream effector signaling and driving therapeutic resistance in RAS-mutated cancers. The contributions of wild-type RAS to proliferation and transformation in RAS-mutated cancer cells places renewed interest in upstream signaling molecules, including the RasGEFs SOS1 and 2, as potential therapeutic targets in RAS-mutated cancers. RAS isoforms have a hierarchy POSTED: 6/29/2020
Headshots of Siqi Li, David MacAlpine and Chris Counter

RAS Mutation Tropism

 Siqi Li is a graduate student in the laboratory of Dr. Chris Counter at Duke University, and is the lead author on the described study regarding the RAS mutation tropism of urethane. David MacAlpine is an Associate Professor in the Department of Pharmacology and Cancer Biology at Duke University. His laboratory focuses on elucidating the mechanisms of genetic and epigenetic inheritance using genomic and computational approaches. Chris Counter is a Professor of Pharmacology and Cancer Biology at Duke University. His laboratory is interested in understanding how oncogenic mutations in RAS genes initiate and promote tumorigenesis. “Why do we get cancer?” remains one of the most fundamental yet intractable questions in cancer biology. The answer may lie, at least in part, in understanding how the process of tumorigenesis first begins. However trying to capture that one single, ostensibly random mutagenic event, in a single gene, in a single cell, decades before POSTED: 5/26/2020