New Model Predicts Immunotherapy Resistance

Resistance to cancer drugs presents a significant barrier to achieving remission and improving survival. Instead of prescribing different drugs in an attempt to overcome treatment resistance, a better approach would predict how cancer cells could mutate in response to a certain drug and co-administer a treatment to block that from happening. Unfortunately, this treatment strategy is not yet possible.

Researchers recently achieved progress towards making this approach a reality by developing a novel method that can predict the paths of resistance for cancer treatments, including immunotherapy. In a study published by Oncogene, the authors also applied this model to one of the most common cancer genes.

The KRAS gene is mutated in approximately 20% of human cancers and is a major driver of pancreatic, colorectal, and lung cancers. KRAS is known to undergo further mutation following successful chemotherapy, radiation, or other therapies.

The authors specifically investigated whether new targeted therapies could inhibit the KRAS G12C variant.

First, they sequenced KRAS-positive lung tumors to determine other oncogenic mutations that result in immunotherapy resistance, according to the study.

The researchers also assessed new KRAS mutations that develop after targeted treatments.

“The treatment initially appears to successfully target a specific mutation in KRAS,” said researcher Jeffrey Townsend, PhD. “But, other mutations can appear down the road. By assessing the tumor's potential to reinvent itself after therapy, our findings inform us on how to combine therapies to intervene before cancer comes back in full force.”

Included in the study were data from a national database of tumor sequences and sequences discovered during previous studies.

Equipped with this information, the researchers developed a framework that has the potential to predict the typical pathways cancer cells may use to resist new targeted immunotherapies, according to the study.

The authors were successful in their efforts to prevent resistance and inhibit KRAS G12C to prevent cancer development.

The study findings offer insight into new mutations likely to resist treatments based on the degree that specific mutations drive the growth and evolution of cancer, as well as the potential of the therapeutic that may be able to stop deviant gene function.

“Currently, we treat tumors with medication to target and inhibit the tumor as is, but not to prevent the future evolution of tumors into resistant forms,” Dr Townsend said. “We need to develop techniques and drugs that not only target the mutations that we know are there, but that also stop the evolution of the tumor.”

The results suggest that combinations of multiple drugs that inhibit the emergence of resistant disease could be used to overcome cancer, according to the study.