Broad FAK inhibition decreased pancreatic cancer stroma and synergises with chemo and immunotherapy

Version française

Pancreatic cancer is known to have a dense stromal compartment which is thought to block therapy penetrance and is known to have direct immunosuppresive properties that inhibit immunotherapies.

A recent paper investigated the effect of a commercially available FAK inhibitor which targets FAK1 and FAK2 in genetically engineered mouse models (GEMs) of pancreatic ductal adenocarcinoma (PDAC) [1]. Key findings were as follows:

  1. FAK inhibition alone increased survival time via tumour stasis
  2. FAK inhibition reduced collagen deposition and numbers of activated fibroblasts
  3. FAK inhibition down-regulated gene expression of fibrosis associated markers
  4. FAK inhibition reduced cancer stem-like cell numbers
  5. FAK inhibition reduced the number of immunosuppresive cells within tumours
  6. FAK inhibition synergised with gemcitibine treatment
  7. FAK inhibition synergised with adoptive T cell transfer to reduce tumour volume and was associated with increased numbers of therapeutic T cell in the tumour.
  8. FAK inhibition synergised with anti-PD1 checkpoint inhibitor
  9. FAK inhibition did not synergise with anti-CTLA4 alone but demonstrated synergy in a gemcitibine treatment background

This paper adds to the growing evidence supporting the importance of reducing the pancreatic cancer stromal density in order to increase the effectiveness of therapeutics that directly target the tumour.

Ref

  1. Jiang, Hong, Samarth Hegde, Brett L Knolhoff, Yu Zhu, John M Herndon, Melissa A Meyer, Timothy M Nywening, et al. ‘Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy’. Nature Medicine, 4 July 2016. doi:10.1038/nm.4123.
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