Researchers develop new strategy to target KRAS mutant cancer

September 14, 2017, University of California - San Diego
cancer
Killer T cells surround a cancer cell. Credit: NIH

Although KRAS is one of the major oncogenes associated with aggressive cancers, drugs designed to block KRAS function have not been able to halt cancer progression in a clinical setting. Until now, KRAS has remained infamously "undruggable."

In a new study, published this month in Cancer Discovery, University of California San Diego School of Medicine researchers report that approximately half of lung and that originate with a KRAS mutation become addicted to the gene as they progress. By understanding the mechanism that causes these cancers to remain dependent on KRAS for survival, they were able to identify a drug capable of targeting it.

"Certain tumors use mutant KRAS to boost their survival by helping them take up nutrients and process toxins, causing them to become addicted to KRAS," said David Cheresh, PhD, UC San Diego School of Medicine Distinguished Professor of Pathology and senior author of the paper. "Other tumors that do not use KRAS in this way can do without it, even though it is needed to initiate . Based on a biomarker we discovered, we now know which cancers will be addicted and which will not."

There are currently no effective treatments for the 95 percent of pancreatic cancers and up to 30 percent of non-small cell lung cancers with KRAS mutations. The team of researchers found that binding of the protein Galectin-3 to the cell surface receptor integrin avb3 amplifies the advantages driven by mutant KRAS, creating a unique vulnerability that could be targeted with an existing drug.

Cheresh and team found that a Galectin-3 inhibitor called GCS-100 was able to kill KRAS-addicted cells in vitro and halt progression of KRAS-addicted tumors in mouse models. Importantly, they discovered that a would respond to the drug only if it was positive for integrin αvb3.

"This may be among the first approaches to successfully target KRAS mutant cancers. Previously, we didn't understand why only certain KRAS-initiated cancers would remain addicted to the mutation," said Cheresh, associate director of innovation and industry alliances at UC San Diego Moores Cancer Center. "Now we understand that expression of integrin αvb3 creates the addiction to KRAS. And it's those addicted cancers that we feel will be most susceptible to targeting this pathway using Galectin-3 inhibitors."

Interrupting the origins of this pathway may be more promising than attempting to block individual KRAS-driven functions, wrote the researchers. Considering that KRAS-addicted cancers were found to be highly sensitive to Galectin-3 inhibitors in preclinical models, the next step would be to clinically test a currently available Galectin-3 inhibitor in patients whose tumors express both mutant KRAS and αvb3, a companion biomarker that predicts response.

"KRAS mutations impact a large number of patients with cancer. If a patient has a KRAS mutant cancer, and the cancer is also positive for αvb3, then the patient could be a candidate for a therapeutic that targets this pathway," said Cheresh. "Our work suggests a personalized medicine approach to identify and exploit KRAS addicted tumors, providing a new opportunity to halt the progression of tumors that currently have no viable targeted therapeutic options."

Explore further: Combination therapies for drug-resistant cancers

More information: Laetitia Seguin et al, Galectin-3, a druggable vulnerability for KRAS-addicted cancers, Cancer Discovery (2017). DOI: 10.1158/2159-8290.CD-17-0539

Related Stories

Combination therapies for drug-resistant cancers

October 10, 2011
Some cancers can be effectively treated with drugs inhibiting proteins known as receptor tyrosine kinases, but not those cancers caused by mutations in the KRAS gene. A team of researchers led by Jeffrey Engelman, at Massachusetts ...

Researchers investigate new strategy to block growth of colon cancer cells

September 21, 2016
Researchers from Boston University School of Medicine (BUSM) have discovered a possible strategy to treat colon cancers that are caused by the mutant KRAS gene, which is responsible for approximately half of all colon cancer ...

MicroRNA specifically kills cancer cells with common mutation

October 3, 2016
Approximately 20 percent of all human cancers have mutations in a gene called KRAS. KRAS-mutant cancers are among the most difficult to treat, with poor survival and resistance to chemotherapy. Researchers at University of ...

KRAS gene mutation and amplification status affects sensitivity to antifolate therapy

April 4, 2012
Testing patients with non-small cell lung cancer for both mutations and amplifications of the KRAS gene prior to therapy may help to predict response to treatment with antifolates, according to the updated results of a preclinical ...

Potential treatment target for KRAS-mutated colon cancer found

February 16, 2012
Researchers from the Massachusetts General Hospital (MGH) Cancer Center have identified a new potential strategy for treating colon tumors driven by mutations in the KRAS gene, which usually resist both conventional and targeted ...

Recommended for you

Researchers discover novel mechanism linking changes in mitochondria to cancer cell death

February 20, 2018
To stop the spread of cancer, cancer cells must die. Unfortunately, many types of cancer cells seem to use innate mechanisms that block cancer cell death, therefore allowing the cancer to metastasize. While seeking to further ...

Stem cell vaccine immunizes lab mice against multiple cancers

February 15, 2018
Stanford University researchers report that injecting mice with inactivated induced pluripotent stem cells (iPSCs) launched a strong immune response against breast, lung, and skin cancers. The vaccine also prevented relapses ...

Induced pluripotent stem cells could serve as cancer vaccine, researchers say

February 15, 2018
Induced pluripotent stem cells, or iPS cells, are a keystone of regenerative medicine. Outside the body, they can be coaxed to become many different types of cells and tissues that can help repair damage due to trauma or ...

Team paves the way to the use of immunotherapy to treat aggressive colon tumors

February 15, 2018
In a short space of time, immunotherapy against cancer cells has become a powerful approach to treat cancers such as melanoma and lung cancer. However, to date, most colon tumours appeared to be unresponsive to this kind ...

Can our genes help predict how women respond to ovarian cancer treatment?

February 15, 2018
Research has identified gene variants that play a significant role in how women with ovarian cancer process chemotherapy.

First comparison of common breast cancer tests finds varied accuracy of predictions

February 15, 2018
Commercially-available prognostic breast cancer tests show significant variation in their abilities to predict disease recurrence, according to a study led by Queen Mary University of London of nearly 800 postmenopausal women.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.