New discovery maps how mutant colorectal tumors adapt to KRAS inhibitors

A new preclinical study led by researchers at The University of Texas MD Anderson Cancer Center and Weill Cornell Medicine has uncovered genetic and cell-state adaptive mechanisms that drive resistance to KRAS inhibitors in patients with KRAS-mutant colorectal cancer.

These findings suggest that targeting early inflammatory responses by adding TBK1 blockade with KRAS inhibition may be a promising combination strategy to overcome treatment resistance.

The study, published today in Cancer Cell, was 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 Medicine. Lukas Dow, Ph.D., professor of medicine at Weill Cornell Medicine, served as co-corresponding author alongside Alonso Martinez.

Our findings uncovered the genetic and cell-state shifts that colorectal tumors use to escape KRAS inhibition. Targeting the adapted early inflammatory response may be the key to stopping resistance and improving the effectiveness of KRAS therapies for these patients."

Alonso Martinez, MD, Assistant Professor, Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center

What are KRAS mutations?

KRAS is the most commonly mutated cancer-associated gene in colorectal cancer, with mutations found in nearly half of all cases. However, only a fraction of KRAS-mutant cancers respond to treatment with the KRAS inhibitors adagrasib and sotorasib, and patients often have short-lived responses and a poor prognosis. Studies have suggested that treatment might cause secondary pathway mutations that may add to this resistance, but it remains unclear.

To understand further, 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 at disease progression. They also tested preclinical organoid models that were resistant to KRAS inhibitors. 

What did the researchers learn about KRAS inhibitor resistance?

The researchers found that while some resistant cells acquire secondary mutations, others change their behavior, or cell-state, to survive. This means that resistance does not come from a single source, but from both genetic and non-genetic factors often coexisting in the same tumor.

In the early, on-treatment patient samples, investigators found that KRAS inhibitors trigger an early alarm response in cancer cells that turn on inflammation-related signals to help them adapt and survive.

Blocking TBK1 reduced that early inflammatory response and overcame treatment resistance in preclinical models, sensitizing cells to KRAS inhibition.

What does this mean for patients with KRAS-mutant colorectal cancer?

The study suggests that targeting early inflammatory responses may offer a more durable approach than focusing solely on secondary genetic mutations. While further clinical studies are needed, combinations that pair KRAS inhibitors with TBK1 blockade could be a promising therapeutic approach to help prevent or delay resistance in patients with KRAS-mutant colorectal cancer.