Menu

Mutant RAS Proteins Team Up for Oncogenicity

Mice with cancer whose KRAS proteins couldn’t link together had much better survival outcomes than those whose oncogenic mutant paired with wild-type KRAS.

Apr 1, 2018
Jim Daley

DANGEROUS DIMERS: Linking mutant KRAS proteins with normal partners can make lung cancer (dark splotches) resistant to anticancer drugs. © iSTOCK.COM/OG PHOTO

EDITOR'S CHOICE IN ONCOLOGY

THE PAPER
C. Ambrogio et al., “KRAS dimerization impacts MEK inhibitor sensitivity and oncogenic activity of mutant KRAS,” Cell, 172:857-68.e15, 2018.

BAD ACTOR
Genes in the RAS family regulate cell growth and differentiation, and mutations can render them oncogenic. One such proto-oncogene, KRAS, frequently turns up in human cancers, including lung cancer, and is associated with resistance to chemotherapies including MEK inhibitors.

PAIRING UP
Some proteins encoded by RAS genes appear to function as dimers—linked pairs of identical molecules. Pasi Jänne, a medical oncologist at Dana-Farber Cancer Institute, used a fluorescence resonance energy transfer (FRET) assay to find that the KRAS protein does, too. They then fashioned a mutant KRAS that was dimerization-deficient.

PARTNERS IN CRIME
Jänne and colleagues compared tumor development in mice with one copy of oncogenic KRAS and one copy of either wild-type KRAS or one that couldn’t dimerize. The mice with dimerization-deficient KRAS fared much better, suggesting that oncogenic KRAS must dimerize with wild-type KRAS to function pathogenically.

GETTING IN THE MIDDLE
“Most of the efforts so far on KRAS-mutant cancers have focused on trying to directly target KRAS itself, which has been a challenge, or to target immediate KRAS effector pathways,” says Jänne. Therapeutically targeting KRAS dimerization instead would be mutation-independent and pathway-specific, he says.

Marie Evangelista, an oncology researcher at Genentech, notes that the strategy comes with its own hurdles. “It’s unclear whether there are going to be any small molecules that can target that interface” between KRAS monomers, she says. “We’re going to need to have a better understanding of how that interface is formed to find out if there are any opportunities to really go after it.”
 

January 2019

Cannabis on Board

Research suggests ill effects of cannabinoids in the womb

Marketplace

Sponsored Product Updates

FORMULATRIX® digital PCR technology to be acquired by QIAGEN
FORMULATRIX® digital PCR technology to be acquired by QIAGEN
FORMULATRIX has announced that their digital PCR assets, including the CONSTELLATION® series of instruments, is being acquired by QIAGEN N.V. (NYSE: QGEN, Frankfurt Stock Exchange: QIA) for up to $260 million ($125 million upfront payment and $135 million of milestones).  QIAGEN has announced plans for a global launch in 2020 of a new series of digital PCR platforms that utilize the advanced dPCR technology developed by FORMULATRIX combined with QIAGEN’s expertise in assay development and automation.
Application of CRISPR/Cas to the Generation of Genetically Engineered Mice
Application of CRISPR/Cas to the Generation of Genetically Engineered Mice
With this application note from Taconic, learn about the power that the CRISPR/Cas system has to revolutionize the field of custom mouse model generation!
Translational Models of Obesity, Dysmetabolism, Diabetes, and Complications
Translational Models of Obesity, Dysmetabolism, Diabetes, and Complications
This webinar, from Crown Bioscience, presents a unique continuum of translational dysmetabolic platforms that more closely mimic human disease. Learn about using next-generation rodent and spontaneously diabetic non-human primate models to accurately model human-relevant disease progression and complications related to obesity and diabetes here!
BiochemAR: an augmented reality app for easy visualization of virtual 3D molecular models
BiochemAR: an augmented reality app for easy visualization of virtual 3D molecular models
Have you played Pokemon Go? Then you've used Augmented Reality (AR) technology! AR technology holds substantial promise and potential for providing a low-cost, easy to use digital platform for the manipulation of virtual 3D objects, including 3D models of biological macromolecules.