The KRAS gene provides instructions for making the K-Ras protein, which plays a role in cell signaling. This protein helps regulate cell growth, division, and survival by acting as a molecular switch within the RAS/MAPK pathway. Normally, K-Ras turns on when cells need to grow or divide and turns off when these processes are complete, maintaining a balance in the body’s tissues.
A “mutation” refers to a change in the DNA sequence of a gene. When mutations occur in the KRAS gene, the K-Ras protein can become overactive, leading to uncontrolled cell growth. Such mutations are common in various cancers, including colon, lung, and pancreatic cancers, making KRAS a significant area of research in oncology.
Understanding KRAS Mutations in Colon Cancer
When a KRAS gene mutation occurs, it transforms the normal KRAS gene into an “oncogene,” which can cause normal cells to become cancerous. This mutation results in a K-Ras protein that is constantly active, remaining “on” even when not needed. This continuous activation leads to uncontrolled cell proliferation, a hallmark of cancer. The mutated K-Ras protein is locked in an active state, promoting unchecked cellular processes. This “gain-of-function” drives increased cell survival and metabolic changes, laying the groundwork for tumor formation.
KRAS mutations are found in approximately 38% of colorectal cancer (CRC) cases globally. The presence of these mutations influences cellular pathways and is a factor in the behavior and progression of colorectal cancer. Tumors developing on the right side of the colon may have a higher likelihood of harboring KRAS mutations.
Detecting KRAS Mutations
Detecting KRAS mutations in colon cancer patients is necessary to guide treatment decisions. These mutations are primarily identified through molecular diagnostic testing performed on tumor tissue samples, typically obtained from a biopsy or surgical removal.
Common techniques include Polymerase Chain Reaction (PCR) and next-generation sequencing (NGS). PCR-based methods offer high sensitivity, while NGS can detect many mutations simultaneously but generally has lower sensitivity.
Tests are performed at diagnosis or if cancer recurs, as KRAS mutation status directly impacts targeted therapy effectiveness. Liquid biopsies, which test circulating tumor DNA (ctDNA) from blood plasma, are also emerging as a less invasive alternative for monitoring disease progression and treatment response.
Treatment Strategies for KRAS-Mutated Colon Cancer
The presence of a KRAS mutation influences the selection of therapies for colon cancer. Historically, standard targeted therapies, particularly epidermal growth factor receptor (EGFR) inhibitors like cetuximab and panitumumab, have been ineffective in patients with KRAS-mutated colorectal cancer. Studies have shown that KRAS mutations can render anti-EGFR antibodies ineffective, sometimes leading to acquired resistance.
The ineffectiveness of EGFR inhibitors in KRAS-mutated tumors stems from KRAS being a downstream component of the EGFR signaling pathway. When KRAS is mutated and constantly active, it bypasses the need for upstream EGFR activation, rendering EGFR inhibition futile.
Despite challenges, research continues to advance. Emerging targeted therapies are designed to inhibit mutated KRAS, particularly the KRAS G12C mutation. While no FDA-approved treatments exist specifically for non-KRAS G12C activating RAS mutations in colon cancer, KRAS-mutant cancers may respond to MEK- or ERK-targeted inhibitors.
Ongoing clinical trials are investigating novel KRAS G12C inhibitors, often in combination with other agents. Other investigational agents are also in development, exploring different mechanisms to target mutated KRAS proteins. These new therapies aim to directly interfere with the overactive signaling caused by the mutated KRAS protein.