FAK-inhibition opens the door to checkpoint immunotherapy in Pancreatic Cancer
© The Author(s). 2017
Received: 3 November 2016
Accepted: 1 February 2017
Published: 21 February 2017
Immunotherapy has had remarkable success in the treatment of some cancer types. However, pancreatic cancer has remained largely refractory to immunotherapy, including immune checkpoint inhibitors. Recently, Jiang and colleagues identified a key role for FAK in regulating the composition of the fibrotic and immuno-suppressive pancreatic tumour niche, and showed that FAK inhibitors can be used in combination with immune checkpoint blockade and gemcitabine chemotherapy to significantly delay pancreatic tumour progression. This study further supports the use of FAK inhibitors in combination with immunotherapy.
KeywordsFAK Immunotherapy Checkpoint blockade Pancreatic cancer
Despite our increased understanding of the pathology of pancreatic cancer, prognosis remains sadly limited. In the United Kingdom, 1-year survival for pancreatic adenocarcinoma presentations is just 21% and 5-year survival just 3% (Cancer Research UK) “(http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer)”. As a result, pancreatic cancer is the 4th to 5th most common cause of cancer death in the UK & US, and is predicted to be the second commonest cause by 2020. Improvements in combination chemotherapy for the fittest patients has come at the cost of significant toxicity, while novel agents have not yet made an impact. Harnessing the body’s own immune system to kill cancer cells has shown promise for a growing number of cancer types, most notably changing the treatment landscape of melanoma . However, pancreatic cancer has remained largely refractory to immunotherapy, including immune checkpoint inhibitors . In a recent issue of the journal Nature Medicine, Jiang and colleagues identify that inhibition of the non-receptor tyrosine kinase, Focal Adhesion Kinase (FAK), can sensitise genetically engineered mouse (GEM) models of pancreatic cancer to the anti-tumour effects of immune checkpoint blockade . They show that this synergistic activity is underpinned by reprogramming of the fibrotic and immuno-suppressive pancreatic tumour microenvironment (TME) in response to treatment with a small molecule FAK kinase inhibitor, and that this is at least in part mediated through FAK-dependent regulation of chemokine expression. This work elegantly illustrates the potential for FAK kinase inhibitors to work alongside immunotherapy.
FAK reprograms the immuno-suppressive pancreatic tumour niche
FAK inhibition synergises with immune checkpoint blockade to improve survival time
In seeking to explore the therapeutic value of FAK-dependent changes in the immuno-suppressive tumour environment, Jiang and colleagues made excellent use of the KPC and KPPC GEM models of pancreatic cancer. These tumours did not respond to the combination of anti-CTLA-4 and anti-PD-1, reflecting the outcomes of clinical trials . However, combination with VS-4718 , one of a number of FAK kinase inhibitors in clinical development , and gemcitabine, one of the standard of care chemotherapies for pancreatic cancer, led to a synergistic and significant anti-tumour response and even long-term survival of a small number of mice from the cohort receiving this treatment (Fig. 1). These results are extremely encouraging and further support the rationale for FAK/immunotherapy combinations to be tested in the clinic. Furthermore, they provide additional evidence that immunotherapy may yet work in pancreatic cancer, if the right combination of agents can be found. However, clinical translation of this 4-way combination may require to be staged in order to fully understand the contribution of each agent and the potential toxicity each will add. For example, it is already established that the combination of anti-CTLA-4 and anti-PD-1 can result in potentially severe immune-mediated side-effects that require careful clinical management , prompting exploration of de-escalated dosing and/or scheduling. Clinical trials combining anti-PD-1 with gemcitabine are already underway, and similar trials incorporating FAK inhibitors have either started or are due to start soon. This is the first time FAK inhibitors have been tested in combination with immunotherapy and the preclinical data are very encouraging. However, we do not yet know if this is the optimal combination. Future studies will need to address this in detail, both in terms of efficacy and tolerability, for translation to the clinic.
The work reported by Jiang and colleagues has seen rapid clinical translation, and has resulted in a clinical trial to test the safety, tolerability, and anti-tumour efficacy of the FAK inhibitor defactinib in combination with pembrolizumab (anti-PD-1) and gemcitabine in advanced pancreatic cancer (clinicalTrials.gov NCT02546531). This will run alongside a further clinical trial that stemmed from our work, which will aim to assess the safety, tolerability, and anti-tumour efficacy of defactinib in combination with pembrolizumab in pancreatic cancer, non-small cell lung cancer, and mesothelioma (clinicalTrials.gov NCT02758587). With clinical testing now underway, we look forward to determining whether the highly encouraging pre-clinical data will translate into clinical benefit in treating these cancers of high unmet need. A key aspect of this ongoing work is the loop back to the laboratory, exploring those real-life biological effects, thereby refining and optimising future combination immunotherapy.
Anti- cytotoxic T-Lymphocyte associated protein 4
Anti-programmed death receptor 1
Focal adhesion kinase
Fibroblast activation protein
Genetically engineered mouse
Myeloid derived suppressor cells
Squamous cell carcinoma
Availability of data and materials
AS drafted the manuscript and figure. SS contributed to drafting and editing the manuscript. SA contributed to drafting and editing the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Wolchok JD, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33.View ArticlePubMedGoogle Scholar
- Kunk PR, et al. From bench to bedside a comprehensive review of pancreatic cancer immunotherapy. J Immunother Cancer. 2016;4:14.View ArticlePubMedPubMed CentralGoogle Scholar
- Jiang H, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22(8):851–60.View ArticlePubMedPubMed CentralGoogle Scholar
- McLean GW, et al. The role of focal-adhesion kinase in cancer - a new therapeutic opportunity. Nat Rev Cancer. 2005;5(7):505–15.View ArticlePubMedGoogle Scholar
- Serrels A, et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell. 2015;163(1):160–73.View ArticlePubMedPubMed CentralGoogle Scholar
- Tavora B, et al. Endothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy. Nature. 2014;514(7520):112–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Stokes JB, et al. Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Mol Cancer Ther. 2011;10(11):2135–45.View ArticlePubMedPubMed CentralGoogle Scholar
- Shapiro IM, et al. Merlin Deficiency Predicts FAK Inhibitor Sensitivity: A Synthetic Lethal Relationship. Sci Transl Med. 2014;6(237):237ra68.View ArticlePubMedPubMed CentralGoogle Scholar
- Lee BY, et al. FAK signaling in human cancer as a target for therapeutics. Pharmacol Ther. 2015;146:132–49.View ArticlePubMedGoogle Scholar