Researchers from Weill Cornell Medicine and MD Anderson Cancer Center have uncovered a surprising reason why many colorectal cancers stop responding to targeted drugs.
The scientists found that cancer cells can activate an internal inflammatory survival program that helps them escape treatment.
The study, published in the journal Cancer Cell, may help researchers design more effective therapies that prevent drug resistance and improve survival for colorectal cancer patients.
Colorectal cancer is one of the leading causes of cancer-related deaths around the world. Although doctors now have better treatments than ever before, many tumors eventually become resistant to therapy, making the disease difficult to control over the long term.
One important target in colorectal cancer is a gene called KRAS. Nearly half of colorectal cancer patients carry mutations in this gene. KRAS mutations cause cells to divide uncontrollably, fueling tumor growth.
To fight this process, scientists developed drugs called KRAS inhibitors. These medicines attach to the abnormal KRAS protein and shut down its activity. For many patients, the drugs initially shrink tumors and slow disease progression.
However, the benefits often do not last. Tumors frequently return after treatment because cancer cells adapt and become resistant.
To understand why this happens, researchers examined colon tumor samples collected from patients before treatment, during therapy, and after resistance developed.
The study was led by Dr. Lukas Dow from Weill Cornell Medicine, together with collaborators from MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center.
The scientists analyzed both DNA mutations and gene activity inside tumor cells. They expected to find many new genetic mutations driving resistance. Surprisingly, the tumors showed relatively few major new mutations.
Some tumors did gain additional copies of the KRAS gene itself, but this did not fully explain why resistance was developing so quickly.
The researchers then turned their attention to non-genetic adaptation. Unlike mutations, non-genetic changes do not permanently alter DNA. Instead, they affect how cells respond to stress and which genes become active.
The scientists discovered that KRAS inhibitor treatment caused cancer cells to activate genes linked to inflammation and tissue repair.
This inflammatory response appeared very early after treatment started. In some cases, the inflammatory signals later decreased once resistance became fully established.
To investigate further, researchers studied hundreds of thousands of individual cells from patient tumors. They consistently observed increased inflammation-related gene activity inside cancer cells.
The team initially suspected immune cells surrounding the tumors might be causing the inflammatory changes. However, laboratory experiments suggested the tumor cells themselves were producing the inflammatory signals.
The scientists created organoids, which are small three-dimensional tumor models grown in the laboratory from colorectal cancer cells. These organoids contained only cancer cells and no surrounding immune cells.
Even in these isolated models, KRAS inhibitors still triggered inflammation-related activity inside the tumor cells.
This finding was important because it showed the cancer treatment itself may unintentionally push tumors into a protective survival state.
Researchers then searched for ways to block this inflammatory response.
They identified a protein called TBK1, which plays a major role in inflammation signaling. When scientists combined a TBK1-blocking drug with a KRAS inhibitor, tumor growth slowed much more strongly than when either treatment was used alone.
The results suggest that targeting inflammation inside tumor cells may help stop cancers from adapting to therapy.
According to Dr. Dow, one advantage of this strategy is that it may avoid broadly suppressing the immune system. Instead of weakening the body’s overall immune defenses, the treatment specifically targets the tumor’s own internal stress signals.
The findings may have major implications for cancer treatment in the future. Many targeted cancer drugs work well initially but fail over time because tumors evolve and adapt.
This study suggests inflammation may be one of the hidden survival tools cancer cells use to resist treatment.
Researchers believe future therapies may need to attack tumors from multiple directions at the same time. Blocking both KRAS activity and inflammatory adaptation may give doctors a better chance of keeping tumors under control for longer periods.
The study also highlights how cancer cells are far more flexible than scientists once believed. Tumors do not rely only on permanent genetic mutations. They can also temporarily change their behavior to survive stressful conditions such as drug treatment.
Although the research was conducted in preclinical models and more studies are still needed, the findings offer an important new direction for colorectal cancer therapy.
Future research will explore whether combining KRAS inhibitors with anti-inflammatory drugs can improve patient outcomes in clinical trials.
Overall, the study provides a deeper understanding of how colorectal tumors escape treatment and offers hope that smarter drug combinations may one day reduce relapse and extend survival for cancer patients.
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Source: Weill Cornell Medicine.
