Scientists have made an important discovery about why some colorectal cancers quickly become resistant to treatment.
Researchers from Weill Cornell Medicine and MD Anderson Cancer Center found that tumors may survive treatment not only through genetic mutations, but also by activating inflammation-related survival programs inside cancer cells.
The findings were published in the journal Cancer Cell and could help researchers develop better ways to treat colorectal cancer and prevent drug resistance in the future.
Colorectal cancer is one of the most common cancers worldwide. It affects the colon or rectum and can become life-threatening if it spreads to other organs.
Doctors have developed many treatments for the disease, including surgery, chemotherapy, targeted drugs, and immunotherapy. However, one of the biggest challenges in cancer treatment is that tumors often adapt and stop responding to therapy over time.
Nearly half of colorectal cancer patients carry a mutation in a gene called KRAS. This mutation causes cells to grow and divide uncontrollably, helping tumors form and spread. Because of this, scientists developed KRAS inhibitors, drugs designed to block the abnormal KRAS protein and stop tumor growth.
At first, these drugs can work very well. Tumors often shrink when treatment begins. But unfortunately, many patients eventually relapse because the cancer becomes resistant to the medication.
The new study aimed to understand exactly how this resistance develops.
The research was led by Dr. Lukas Dow, a professor of biochemistry in medicine at Weill Cornell Medicine. His team worked together with scientists from MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center.
Researchers analyzed tumor biopsy samples from colorectal cancer patients before treatment, during treatment, and after resistance developed. They examined both genetic changes and gene expression patterns to understand how the tumors were adapting.
At first, the scientists expected to find many new genetic mutations that explained the resistance. They did discover that some tumors gained extra copies of the KRAS gene itself. However, surprisingly, major new mutations were relatively rare.
This led the researchers to investigate something else called non-genetic adaptation. Non-genetic changes do not alter the DNA sequence directly. Instead, they change how cells behave and which genes are turned on or off.
The team discovered that cancer cells treated with KRAS inhibitors activated inflammation-related pathways very early during treatment. Genes linked to inflammation became highly active inside tumor cells shortly after treatment began.
To study this more closely, the scientists examined hundreds of thousands of individual cells taken from tumors. They consistently found increased inflammatory activity during the early phase of treatment.
At first, researchers wondered whether immune cells surrounding the tumor were causing the inflammation. But additional experiments showed that the cancer cells themselves were producing these inflammatory signals.
The scientists grew miniature tumor models called organoids in the laboratory. These organoids contained only cancer cells and no immune cells. Even in this simplified environment, the same inflammation-related gene activity appeared after treatment with KRAS inhibitors.
This suggested that the cancer drugs themselves were triggering survival responses inside tumor cells.
Dr. Dow explained that when the researchers blocked these inflammatory signals, tumors became less resistant to treatment. This finding suggests inflammation may help cancer cells survive therapy and eventually escape treatment.
The researchers then searched for drugs that could block the inflammatory pathway involved in resistance. They identified a protein called TBK1 as a promising target.
When scientists combined a TBK1 inhibitor with a KRAS inhibitor in patient-derived tumor models, cancer growth slowed much more effectively than when either drug was used alone.
Importantly, the inflammatory signals appeared to come mainly from inside the tumor cells rather than from the immune system as a whole. This means future treatments may be able to target the tumor’s internal survival system without broadly suppressing the body’s immune defenses.
The study highlights how complicated cancer resistance can be. Tumors may use both genetic and non-genetic strategies to survive treatment. Even if only a small number of cells develop mutations, many cancer cells may still adapt through temporary inflammatory responses.
The findings may also help explain why targeted cancer drugs often work well at first but lose effectiveness over time.
Researchers believe combining KRAS inhibitors with anti-inflammatory approaches could potentially improve long-term outcomes for patients with colorectal cancer. Future studies will now focus on testing these combination therapies in additional preclinical models and eventually in human clinical trials.
Although the research is still in its early stages, scientists say it represents an important step toward understanding and overcoming drug resistance in colorectal cancer.
The study also reflects a growing shift in cancer research. Scientists increasingly recognize that cancer is not driven only by permanent DNA mutations. Temporary cellular changes, stress responses, and inflammation may also play major roles in how tumors survive and evolve.
Overall, the research offers hope that smarter combination therapies may one day help patients stay responsive to treatment longer and reduce the chances of cancer relapse.
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Source: Weill Cornell Medicine.
