Targeting tumor-specific inflammatory process may prevent drug resistance in colon cancer
· News-MedicalChemotherapy drugs that target a common mutation in colorectal cancer rapidly lose efficacy in patients, leading to relapse. According to a new preclinical study by Weill Cornell Medicine and MD Anderson Cancer Center investigators, colorectal tumors often find multiple ways to survive treatment, including additional genetic mutations and activation of cellular pathways typically associated with inflammation and regeneration. Targeting this tumor-specific inflammatory process could enhance the efficacy of some anticancer therapies and prevent drug resistance.
Almost half of colorectal cancer patients have a mutation in the KRAS gene that pushes normal cells to grow and divide uncontrollably, forming tumors. KRAS inhibitors bind to mutated KRAS proteins, inactivating them and halting the runaway cell division that drives tumor growth in colon cancer. The study, published May 21 in Cancer Cell, showed that tumors treated with KRAS inhibiting drugs can evade death by setting off cellular changes associated with inflammation.
"We see a lot of genetic changes in tumors of patients who are undergoing treatment, but we also see non-genetic adaptive responses in drug-resistant tumors," said Dr. Lukas Dow, professor of biochemistry in medicine at Weill Cornell, who led the study. "The genetic changes often happen in only a small subset of cells, but the inflammatory adaptive response is more general. When we inhibit that process in preclinical models, less drug resistance develops."
Co-first authors Dr. Salvador Alonso, now an assistant professor in gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, and Kevan Chu, a graduate student in the Dow lab, helped direct the study in collaboration with Dr. Rona Yaeger at Memorial Sloan Kettering Cancer Center.
Tumor survival mechanisms
To learn how tumors bypass the effects of KRAS inhibitors, the researchers analyzed mutations and gene expression-which genes are turned "on" or "off" in a cell-in colon biopsy samples from patients taken before, during, and after treatment.
Dr. Salvador Alonso, assistant professor in gastrointestinal medical oncology, The University of Texas MD Anderson Cancer CenterWe wanted to understand exactly how tumors escape these drugs, so we could get ahead of it. What we found was more complex-and more instructive-than we anticipated."
The team found that while some resistant tumors carried extra copies of KRAS, the drug target itself, acquired mutations were rare. Interestingly, some tumors had both genetic changes and non-genetic changes, highlighting the challenge of identifying and tackling the causes of treatment failure. Genetic changes are alterations to the DNA sequence, the body's biological "instruction manual." Non-genetic changes affect how those instructions are used without changing the underlying DNA code itself.
Next, the researchers delved into whether immune cells recruited to the tumor site to fight the cancer could cause the uptick in inflammatory factors, or the cancer cells themselves were to blame. They conducted experiments on organoids, which are malignant colorectal cells grown in a 3-dimensional matrix in a dish and not exposed to any other cells. The researchers observed the same increase in inflammation-related gene expression soon after treatment.
"When we block these inflammatory signals in organoids treated with KRAS inhibitors, we see less drug resistance," said Dr. Dow, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell. "This result suggests that the drug is driving changes within the tumor cells that ultimately contribute to the emergence of resistance to that drug."
Better together
The researchers screened drugs that inhibit kinases involved in inflammation signaling and identified TBK1 as a promising target. When they combined a TBK1 inhibitor with a KRAS inhibitor in patient-derived tumor models, cancer cell growth slowed significantly compared to either drug alone. Importantly, the team showed that the TBK1 inflammatory signal originates inside the tumor cells, so targeting it can disrupt the cancer's internal alarm rather than broadly suppressing a patient's immune defenses.
"Instead of interfering with the immune system at large, we think that selectively blocking the drug-induced inflammatory trigger could prevent tumor cells from adapting to treatment and help improve outcomes with KRAS inhibitors," Dr. Dow said.
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