The KRAS gene is one of the commonly mutated genes in cancer. More than 40% of colorectal cancers have a mutated KRAS gene, or oncogene, that is at least partially responsible for cancer development. Mutated KRAS genes are commonly found in other cancers as well. Researchers at Cancer Center at Beth Israel Deaconess Medical Center (BIDMC), using preclinical mouse models of cancer, have shown for the first time that cancer disease incidence and severity are influenced by both the specific type of KRAS mutation as well as the tissue in which the mutation is located.  

TrialSite News breaks this story down that was published in Cancer Discovery, Cell Reports and Cell Systems.

What is KRAS?

KRAS is a gene that acts as an off/off switch in cell signaling. When it functions normally, it controls cell proliferation. When it is mutated, negative signaling is disrupted. Thus, cells  can continuously proliferate, and often develop into cancer.

What is it called KRAS?

It is called KRAS because it was first identified as an oncogene in Kirsten rAt Sarcoma virus. The viral oncogene was derived from cellular genome. Thus, KRAS gene in cellular genome is called a proto-oncogene.

What is BIDMC’s Breakthrough with KRAS?

Precision medicine isn’t precise enough, reports principal investigator Kevin Kaigis, PhD, Director, Cancer Genetics Program at the Cancer Research Institute at the Cancer Center at BIDMC.  Dr. Kaigis reports that “Basket trials, in which patients with a particular genetic mutation like KRAS are grouped into the same basket and given a drug against the mutation, are not sufficient. Our work shows for the first time that every single mutant form of KRAS differs in terms of cancer-causing ability and downstream signaling of relevant molecular pathways.”

Can you place all KRAS mutant cancers in the same basket?

No. Each allele is actually quite different from one another, reports Kevin Kaigis, who says, “Clinicians need to know exactly which mutation a patient has and create a mutation specific basket for a clinal trial.”

Why do they think different cancers with different mutations will respond differently to drugs?

The group’s study looked at colorectal cancer caused by rare or common KRAS mutations. Homing in on a KRAS mutation associated with a region of the gene known as codon 146, their mouse model showed that animals with the 146 mutation live longer than animals with another type of KRAS mutation, called G12D. Haigis explained “In colon cancer, the 146 mutation doses cause colon cancer, but those colon cancers are much weaker and the mice survive longer.” The team also saw that the proteome, or the signaling pathways, is dramatically different between the two types. He continued, “That’s why we think cancers with different mutations will respond differently to drugs.”

Looking Ahead: What is Next for Haigis and Team?

He recently received an award for the Cancer Research UK Grand Challenge to further study this concept. The concept that no single factor can predict whether a cancer responds to a particular therapy will be key to the future of precision medicine,” he said. “Clinicians and scientists need to know which tissue the cancer comes from, which oncogene is mutated and which allele is created, and the other genes that are mutated; all of that determines if and how well a cancer will respond to a given drug. That is precision medicine and that’s the level we have to get to.”

Lead Research/Investigator

Kevin Kaigis, PhD, Director, Cancer Genetics Program at the Cancer Research Institute at the Cancer Center at BIDMC

Call to Action: This group will continue to study which cancer comes from which oncogene is mutated and which allele is created and what other genes are mutated—all determines if and how cancer will respond to a given drug. This research group will continue to pursue that level of “precision medicine.” Does this align with your interests? Why not follow this group? TrialSite Network can also make an introduction.

Source: EurekAlert!

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