A new preclinical study led by researchers at The University of Texas MD Anderson Cancer Center and Weill Cornell Medicine uncovers adaptive mechanisms of genetic and cellular status in patients with resistance to KRAS inhibitors. class-Mutant colorectal cancer.
These findings suggest that targeting the early inflammatory response by adding TBK1 blockade and KRAS inhibition may be a promising combination strategy to overcome treatment resistance.
This research today cancer cellswas co-led by Salvador Alonso Martinez, M.D., assistant professor of gastrointestinal medical oncology at UT MD Anderson, and Kevan Chu, a graduate student at Weill Cornell Medical College. Dr. Lucas Dow, professor of medicine at Weill Cornell University, served as co-corresponding author with Alonso Martinez.
Our findings reveal genetic and cellular state changes that colorectal tumors exploit to evade KRAS inhibition. Targeting the adaptive early inflammatory response may be the key to preventing resistance and improving the efficacy of KRAS therapy in these patients. ”
Alonso Martinez, MD, Assistant Professor of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center
What is class mutation?
class is the most commonly mutated cancer-related gene in colorectal cancer, being mutated in nearly half of all cases. However, only some classMutated cancers respond to treatment with the KRAS inhibitors adaglasib and sotorasib, but patient responses are often short-lived and the prognosis is poor. Research suggests that treatment may induce secondary pathway mutations that may further increase this resistance, but this remains unclear.
To further understand, the researchers used targeted gene sequencing and single-cell spatial transcriptomics to examine patient-matched clinical samples collected before and during treatment with KRAS inhibitors and during disease progression. They also tested a preclinical organoid model that was resistant to KRAS inhibitors.
What have researchers learned about KRAS inhibitor resistance?
The researchers found that some resistant cells acquire secondary mutations, while others change their behavior or cell state to survive. This means that resistance does not arise from a single cause, but from both genetic and non-genetic factors that often coexist within the same tumor.
Researchers found that in patient samples during early treatment, KRAS inhibitors trigger an early warning response in cancer cells, turning on inflammation-related signals that help cancer cells adapt and survive.
Blocking TBK1 attenuated the early inflammatory response in preclinical models, overcame treatment resistance and rendered cells sensitive to KRAS inhibition.
What does this mean for KRAS-mutant colorectal cancer patients?
This study suggests that targeting the early inflammatory response may offer a more durable approach than focusing solely on secondary genetic mutations. Although further clinical studies are needed, combination therapy combining KRAS inhibitors and TBK1 inhibitors may be a promising therapeutic approach to help prevent or delay resistance in patients with the disease. class-Mutant colorectal cancer.
sauce:
University of Texas MD Anderson Cancer Center
Reference magazines:
Alonso, S., et al. (2026). Co-occurrence of genetic and non-genetic resistance mechanisms to KRAS inhibition in colorectal cancer. cancer cells. DOI: 10.1016/j.ccell.2026.04.009. https://www.cell.com/cancer-cell/abstract/S1535-6108(26)00220-5.
