New research published in Science Translational Medicine identifies an interplay between tumour-intrinsic and tumour-extrinsic factors that drive resistance to treatment in pancreatic ductal adenocarcinoma (PDAC). The findings provide the rationale for combined therapies that target both oncogenic signalling and the tumour microenvironment to overcome PDAC drug resistance.

Inhibitors of the RAS–MAPK pathway hold great promise as a therapeutic strategy for PDAC. However, patients rapidly develop drug resistance, explained in part by upregulation of members of the receptor tyrosine kinase family. The researchers found that the combination of RAS–MAPK inhibitors with inhibitors of focal adhesion kinase (FAK) — a non-receptor tyrosine kinase — reduced tumour growth and increased survival in several mouse models of PDAC to a greater extent than either therapy alone. Single-cell RNA sequencing and cell culture experiments revealed that cancer-associated fibroblasts in the tumour microenvironment are activated by FAK and impair the downregulation of MYC by RAS–MAPK inhibition in PDAC cells, resulting in drug resistance. “This identifies cancer-associated fibroblasts as a novel therapeutic target for overcoming RAS pathway resistance,” explains author Gregory Beatty.