Oncogene-Mechanics Axis: KRAS G12C Confers Agility Enabling Malignant Mechano-responses to Peristalsis in Colorectal Cancer

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

Abstract excerpt

Oncogene activity and mechanical forced individually and collective drive colorectal cancer, yet the integration of these signals is unknown. We used a patented peristalsis bioreactor to determine how oncogenic KRAS G12C mutations alter the cellular response to colonic peristalsis. Although both ehalthy intestinal cells and KRAS G12C cells sensed peristalsis via ERK phosphorylation, their mechano-responses diverged significantly. Peristalsis triggered a 9-fold enrichment of LGR5+ cancer stem cells in KRAS G12C cancer cells, an effect absent in healthy controls. Using Brillouin microscopy, we discovered that KRAS G12C induced a more agile and deformable mechano-phenotype by lowering intracellular viscosity, a state further amplified by peristalsis. This agility allowed KRAS G12C cancer cells to leverage, rather than resist peristalsis, resulting in LGR5 enrichment and malignant progression. Pharmacologic inhibition of KRAS G12C reverse the mechano-phenotype, while introducing KRAS G12C into healthy cells recapitulated it. Our findings identify a novel KRAS oncogene-mechanics axis, suggesting that targeting the cell's mechanical state could be a powerful complement to emerging KRAS-directed therapies.