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Pancreas
Original article
Development of resistance to FAK inhibition in pancreatic cancer is linked to stromal depletion
  1. Hong Jiang1,2,
  2. Xiuting Liu1,
  3. Brett L Knolhoff1,
  4. Samarth Hegde1,
  5. Kyung Bae Lee1,
  6. Hongmei Jiang1,
  7. Ryan C Fields3,4,
  8. Jonathan A Pachter5,
  9. Kian-Huat Lim1,3,
  10. David G DeNardo1,3,6
  1. 1 Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
  2. 2 Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  3. 3 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
  4. 4 Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
  5. 5 Verastem Inc., Needham, MA, USA
  6. 6 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
  1. Correspondence to Dr David G DeNardo, Medicine, Washington University, St. Louis, MO 63132, USA; ddenardo{at}wustl.edu

Abstract

Objective We investigated how pancreatic cancer developed resistance to focal adhesion kinase (FAK) inhibition over time.

Design Pancreatic ductal adenocarcinoma (PDAC) tumours from KPC mice (p48-CRE; LSL-KRasG12D/wt; p53flox/wt) treated with FAK inhibitor were analysed for the activation of a compensatory survival pathway in resistant tumours. We identified pathways involved in the regulation of signal transducer and activator of transcription 3 (STAT3) signalling on FAK inhibition by gene set enrichment analysis and verified these outcomes by RNA interference studies. We also tested combinatorial approaches targeting FAK and STAT3 in syngeneic transplantable mouse models of PDAC and KPC mice.

Results In KPC mice, the expression levels of phosphorylated STAT3 (pSTAT3) were increased in PDAC cells as they progressed on FAK inhibitor therapy. This progression corresponded to decreased collagen density, lowered numbers of SMA+ fibroblasts and downregulation of the transforming growth factor beta (TGF-β)/SMAD signalling pathway in FAK inhibitor-treated PDAC tumours. Furthermore, TGF-β production by fibroblasts in vitro drives repression of STAT3 signalling and enhanced responsiveness to FAK inhibitor therapy. Knockdown of SMAD3 in pancreatic cancer cells abolished the inhibitory effects of TGF-β on pSTAT3. We further found that tumour-intrinsic STAT3 regulates the durability of the antiproliferative activity of FAK inhibitor, and combinatorial targeting of FAK and Janus kinase/STAT3 act synergistically to suppress pancreatic cancer progression in mouse models.

Conclusion Stromal depletion by FAK inhibitor therapy leads to eventual treatment resistance through the activation of STAT3 signalling. These data suggest that, similar to tumour-targeted therapies, resistance mechanisms to therapies targeting stromal desmoplasia may be critical to treatment durability.

  • pancreatic cancer
  • drug resistance
  • TGF-beta
  • pancreatic fibrosis
  • myofibroblasts

https://doi.org/10.1136/gutjnl-2018-317424

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    Footnotes

    • HJ and XL contributed equally.

    • Contributors DGD, HJ and XL conceived and designed the project. HJ conducted transgenic and transplant mouse experiments and treatments. BLK aided with FAK inhibitor and STAT3 inhibitor treatments. HJ and BLK provided KPC and KPPC mice. HJ, XL and KBL performed histology, immunohistochemistry and immunofluorescence on murine and human samples and related analyses. HJ and XL performed RNA interference, MTT, three-dimensional collagen assays, immunoblotting and related analyses. SH and XL performed RNA in situ hybridisation and post-hoc analyses. BLK performed ultrasound detection and real-time PCR. XL, HJ and K-HL performed synergism experiments and analysis. RCF provided TMA samples. JAP provided FAK inhibitor VS-4718 and intellectual input on the project. HJ and XL wrote the manuscript, and DGD and SH revised it.

    • Funding This work was supported by funding awarded to DGD from the National Cancer Institute (P50 CA196510, R01 CA177670, R01 CA203890).

    • Competing interests None declared.

    • Ethics approval The protocol was approved by the Ethics Committee of Washington University School of Medicine.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Patient consent for publication Not required.

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