ROCK Inhibition Primes Tumor Tissue to Sensitize Cells to Chemotherapy

Inoperable pancreatic cancer is often treated with the cytotoxic drugs gemcitabine and nanoparticle albumin–bound paclitaxel (Abraxane), but new treatment strategies are needed to improve patient survival. The Rho GTPases have emerged as potential therapeutic targets, as they regulate the actin cytoskeleton to affect cellular invasion and alter interactions between stromal and cancer cells to induce tissue stiffening and drive tumor progression. Vennin, Chin, and colleagues investigated the use of the Rho kinase (ROCK) inhibitor Fasudil in “priming” the tumor stroma before chemotherapy. Fasudil priming disrupted the integrity of the collagen extracellular matrix (ECM), resulting in a disorganized ECM network with reduced stiffness. In a 3-D organotypic model of pancreatic cancer, priming with Fasudil reduced cell invasion, whereas continuous or late treatment with Fasudil had no significant benefit, indicating that short-term ROCK targeting may be sufficient to suppress pancreatic cancer invasion while minimizing possible side effects. Further, Fasudil priming promoted blood vessel relaxation to enhance delivery of and sensitivity to gemcitabine plus Abraxane. Murine pancreatic cancer cells were engineered to express a CDK1–FRET biosensor to monitor CDK1 activity as a marker of gemcitabine/Abraxane-induced cell-cycle arrest, allowing for evaluation of Fasudil priming in vivo. In pancreatic cancer xenografts, priming with Fasudil before gemcitabine plus Abraxane resulted in reduced fibrillar collagen organization, enhanced CDK1 activation, and improved chemotherapeutic efficacy at primary and secondary sites. Fasudil priming impaired extravasation by reducing cell adhesion, sensitized tumor cells to shear stress, and impaired colonization and fibrotic niche remodeling in the liver, further supporting a role for Fasudil priming in suppressing metastasis. Moreover, Fasudil priming enhanced the efficacy of gemcitabine plus Abraxane in stratified pancreatic cancer patient–derived xenografts, extending survival and delaying metastasis. Altogether, these findings suggest that short-term tumor stroma remodeling may improve chemotherapeutic efficacy, and support further investigation of Fasudil priming to suppress primary and metastatic pancreatic cancers.

Vennin C, Chin VT, Warren SC, Lucas MC, Herrmann D, Magenau A, et al. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci Transl Med 2017;9:eaai8501.