UC studies: Silent mutations, tumor microenvironment may be therapeutic targets

KRAS, the most commonly mutated oncogene in human cancer, is mutated in more than 90% of pancreatic cancers, helping the tumors grow, spread and evade treatment.

Certain KRAS mutations, called “silent” or “synonymous” mutations, have been ignored during clinical testing because they do not change the gene’s amino acid sequence. Researchers including first author Megan Satyadi, MD, examined whether these silent mutations still affected cancer cells.

“Specifically, we wanted to know whether these synonymous variants could alter KRAS biology and influence how cancer cells respond to emerging KRAS-targeted therapies,” said Satyadi, a resident in UC’s Department of Surgery in the College of Medicine working in the lab of Andrew Waters, PhD.

The team found that certain silent KRAS mutations behave more similarly to mutations known to help tumor cells grow than previously thought, increasing KRAS expression and helping tumors develop treatment resistance.

“This challenges the long-standing assumption that all silent mutations are biologically inert and suggests that some patients currently classified as ‘KRAS wild-type’ may in fact have tumors with meaningful oncogenic KRAS activity,” Satyadi said.

Moving forward, the team will work to validate the findings in more clinically relevant systems, such as animal cell models, and define the mechanisms these silent mutations use. More broadly, the research highlights that these so-called “silent” mutations are not truly silent and need to be studied more closely in other cancer cells.

“As precision oncology increasingly relies on genomic classification, our findings suggest that subtle nucleotide changes may have clinically meaningful effects that are currently overlooked,” Satyadi said. “Recognizing these variants could refine how we interpret sequencing results and identify new groups of patients who may benefit from targeted treatment therapies.”

Satyadi will present “Silent KRAS mutations confer altered sensitivity to targeted KRAS inhibition” April 21 at 2 p.m.

Cancer-associated fibroblasts (CAFs) are cells outside a tumor but within the tumor microenvironment that help tumors grow and spread. They can also help cancer cells develop resistance to certain treatments.

Researchers including first author Jie Wang examined how CAFs help melanoma cells develop resistance to BRAF inhibitors, a targeted therapy. 

“We identified a novel β-catenin–TCF–POSTN regulatory axis that drives CAF-mediated resistance to BRAF inhibitors in melanoma,” said Wang, a graduate assistant in the lab of Yuhang Zhang in UC’s James L. Winkle College of Pharmacy. In cells, regulatory axes are pathways where genes, proteins and other cellular material interact to control specific processes.

“Specifically, CAF-derived POSTN, regulated by β-catenin–TCF signaling, promotes extracellular matrix remodeling and enhances melanoma cell survival under therapeutic pressure,” explained Wang.

The findings support a treatment approach that targets both the tumor and CAFs by combining a drug that inhibits β-catenin–TCF interaction and a BRAF inhibitor to help overcome treatment resistance in melanoma.

“This study highlights the importance of tumor-stroma interactions in drug resistance and underscores the potential of targeting the tumor microenvironment,” Wang said. 

Wang will present “POSTN-driven mechanotransduction sustains β-catenin activity in CAFs to promote melanoma progression and drug resistance” April 20 at 2 p.m.