Abstract

We use genetic and chemical intervention and imaging to understand the biological and molecular mechanisms by which adhesion-linked tyrosine kinases promote malignancy, and how best to perturb for therapeutic advantage. Focal Adhesion Kinase (FAK) is a Src-regulated, integrin-effector kinase that is frequently elevated in cancer, and there are a number of small molecule FAK inhibitors currently in clinical development. Gene knockout studies in skin, intestine, and breast cancer models have implicated FAK in epithelial tumour progression and metastasis.

Using mutant Ras-dependent models of Squamous Cell Carcinoma (SCC) and pancreatic cancer, we have uncovered a mechanism that tumour cells use to survive when flux through the integrin/Src/FAK pathway is severely perturbed. Adhesion stress, including that caused by deletion of FAK, promotes selective sequestration of active Src away from integrin adhesions and into intracellular autophagic structures and on for lysosomal degradation. Inhibition of autophagy leads to cancer cell death, demonstrating that selective autophagic targeting of Src (and other oncogenic tyrosine kinases) is an adaptive mechanism to maintain viability, identifying a cancer cell vulnerability that provides a new therapeutic opportunity.

We have also found a novel function for FAK in generating an immunosuppressive and pro-tumorigenic microenvironment. Specifically, FAK activity in cancer cells drives recruitment and/or differentiation of CD4⁺CD25⁺FoxP3⁺ regulatory T-cells, likely through altered transcription of the genes encoding the intra-tumoral cytokines Interleukin-2 (IL-2), Interleukin-10 (IL-10), and Transforming Growth Factor-beta (TGFβ). This suppresses the anti-tumour activity of antigen-primed cytotoxic CD8⁺ T-cells and permits survival, and growth, of FAK-expressing tumours in immune competent hosts. Importantly, cancer cell immune evasion depends on FAK's catalytic activity, and VS-4718, a small molecule FAK kinase inhibitor that is in clinical development, suppresses regulatory T-cells, increases cytotoxic CD8⁺ T-cells and promotes tumour regression and clearance in mice. This identifies an additional mechanism, namely immunomodulation, through which FAK kinase inhibitors may impart anti-tumour efficacy.

Full authorship

¹Margaret Frame, ¹Valerie Brunton, ¹Emma Sandilands, ¹Bryan Serrels, ²Jonathan Pachter, ¹Tom Lund and ¹Alan Serrels 

¹Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, Crewe Road South, University of Edinburgh, UK, EH4 2XR, ²Verastem Inc., Cambridge, MA, USA