FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine

Abstract

BackgroundPancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumours. Treatment options are limited and gemcitabine-based chemotherapy remains the standard of care. Although growing evidence shows that p21-activated kinase 1 (PAK1) plays a crucial role in pancreatic cancer, its role has not been fully elucidated. This study aimed to characterise the expression and functional relevance of PAK1 in pancreatic cancer.MethodsPAK1 expression was measured in pancreatic cancer specimens by immunohistochemistry and in pancreatic cancer cell lines by western blotting. The effect of inhibition of PAK1 by either shRNA knock-down (KD), or by a selective inhibitor, FRAX597, alone or in combination with gemcitabine, on cell proliferation and migration/invasion was measured by thymidine uptake and Boyden chamber assays, respectively. The effect on tumour growth and survival was assessed in orthotopic murine models.ResultsPAK1 was expressed in all human pancreatic cancer samples tested, an7d was upregulated in all pancreatic cancer cell lines tested. PAK1 KD inhibited pancreatic cancer cell growth and survival, and increased sensitivity to gemcitabine treatment. AKT activity and HIF1α expression were also inhibited. FRAX597 inhibited pancreatic cancer cell proliferation, survival, and migration/invasion. When combined with gemcitabine, FRAX597 synergistically inhibited pancreatic cancer proliferation in vitro and inhibited tumour growth in vivo.ConclusionsThese results implicate PAK1 as a regulator of pancreatic cancer cell growth and survival. Combination of a PAK1 inhibitor such as FRAX597 with cytotoxic chemotherapy deserves further study as a novel therapeutic approach to pancreatic cancer treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2057-z) contains supplementary material, which is available to authorized users.

Deciphering the link between PI3K and PAK: An opportunity to target key pathways in pancreatic cancer?

“…Furthermore, PAK1 depletion led to reduced migration and invasion suggesting PAK1 may play a more prominent role in KRAS-independent PDAC. In addition, a further study also confirmed that PAK1 depletion led to reduced proliferation in the PDAC cell lines MiaPaCa2 and Panc1 [120]. Thus, whilst it is clear that PAK1 over expression is present in PDAC tissue compared with normal tissue, its precise in vivo role in carcinogenesis and metastatic spread needs to be investigated further.…”

Targeting p21 activated kinase 1 (Pak1) to PAKup Pancreatic Cancer

“…One possible impeding factor which is difficult to achieve is the selectivity within the PAK family, because of sequence homology among the family members. Although some Pak1 selective inhibitors like IPA-3 [9,[16][17][18][19], FRAX-597 [11,20], G-5555 [12], and Novartis compound 3 [13] have been disclosed, the successful in vivo dose optimization for target specificity and stability is yet to be tested on larger group of animals. …”

“…Recently, several reports [4,9,11,15] unraveled the role of Pak1 in the activation of pancreatic stellate cells (PSCs), its involvement in transforming normal pancreatic cells to PDAC and its ability to modulate drug resistance in pancreatic cancer. All these findings suggest that Pak1-specific inhibitors will prove to be a better adjuvant with the existing chemotherapy modality for PDAC.…”

“…As the earlier pharmacologic inhibitors of Pak1 are not very specific, new Pak1 selective inhibitors such as FRAX-597, G-5555, Novartis compound 3 etc. are been synthesized and are under evaluation for clinical efficacy [11][12][13]. In addition, as suggested by Baker et al [14], it would be worthwhile to identify a reliable Pak1 substrate-specific biomarker for Pak1 inhibitor antitumor activity.…”

Upregulation of P21-Activated Kinase 1 (PAK1)/CREB Axis in Squamous Non-Small Cell Lung Carcinoma

“…PAK1 is involved in the tumorigenesis of several types of cancer. For example, downregulating PAK1 expression with a short-hairpin RNA or treatment with the selective PAK1 inhibitor FRAX597 reduced pancreatic cancer cell growth and survival [3]. Moreover, PAK1 expression is upregulated in prostate cancer, and treatment with the mTOR inhibitor rapamycin slowed cancer cell proliferation by inhibiting PAK1 expression [4].…”