TY - JOUR
T1 - Concurrent HER or PI3K inhibition potentiates the antitumor effect of the ERK inhibitor ulixertinib in preclinical pancreatic cancer models
AU - Jiang, Hongmei
AU - Xu, Mai
AU - Li, Lin
AU - Grierson, Patrick
AU - Dodhiawala, Paarth
AU - Highkin, Maureen
AU - Zhang, Daoxiang
AU - Li, Qiong
AU - Wang-Gillam, Andrea
AU - Lim, Kian Huat
N1 - Funding Information:
K.H. Lim is supported by the 2016 Pancreatic Cancer Action Network– AACR Career Development Award, supported by Laurie MacCaskill, WUSTL Pancreatic Cancer SPORE (NIH/NCI grant 1P50CA196510-01A1), Siteman Cancer Center and The Foundation for Barnes-Jewish Hospital, Concern Foundation Conquer Cancer Now Award, the Washington University Institute of Clinical and Translational Sciences grant (UL1 TR000448 from the NCATS/NIH). A. Wang-Gillam is supported by the WUSTL Pancreatic Cancer SPORE (NIH/NCI grant 1P50CA196510-01A1), Siteman Cancer Center, and The Foundation for Barnes-Jewish Hospital. Q. Li is supported by the National Natural Science Foundation of China (grant 81401735). We thank the WUSTL Digestive Disease Research Core Center (grant P30DK052574 from the NIDDK) for assistance in tissue sections and staining. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/10
Y1 - 2018/10
N2 - Effective treatment for pancreatic ductal adenocarcinoma (PDAC) is an urgent, unmet medical need. Targeting KRAS, the oncogene that is present in >95% of PDAC, is a heavily pursued strategy, but remains unsuccessful in the clinic. Therefore, targeting key effector cascades of KRAS oncopro-tein, particularly the mitogenic RAF-MEK-ERK pathway, represents the next best strategy. However, RAF or MEK inhibitors have failed to show clinical efficacy in PDAC. Several studies have shown that cancer cells treated with RAF or MEK inhibitors adopt multiple mechanisms to reactivate ERK signaling. Therefore, development of ERK-specific inhibitors carries the promise to effectively abrogate this pathway. Ulixertinib (or BVD-523) is a first-in-class ERK-specific inhibitor that has demonstrated promising antitumor activity in a phase I clinical trial for advanced solid tumors with NRAS and BRAF mutations, providing a strong rationale to test this inhibitor in PDAC. In this study, we show that ulixertinib effectively inhibits in vitro growth of multiple PDAC lines and potentiates the cytotoxic effect of gemcitabine. Moreover, we found that PDAC cells treated with ulixertinib upregulates the parallel PI3K-AKT pathway through activating the HER/ErbB family proteins. Concurrent inhibition of PI3K or HER proteins synergizes with ulixertinib in suppressing PDAC cell growth in vitro and in vivo. Overall, our study provides the preclinical rationale for testing combinations of ulixertinib with chemotherapy or PI3K and HER inhibitors in PDAC patients.
AB - Effective treatment for pancreatic ductal adenocarcinoma (PDAC) is an urgent, unmet medical need. Targeting KRAS, the oncogene that is present in >95% of PDAC, is a heavily pursued strategy, but remains unsuccessful in the clinic. Therefore, targeting key effector cascades of KRAS oncopro-tein, particularly the mitogenic RAF-MEK-ERK pathway, represents the next best strategy. However, RAF or MEK inhibitors have failed to show clinical efficacy in PDAC. Several studies have shown that cancer cells treated with RAF or MEK inhibitors adopt multiple mechanisms to reactivate ERK signaling. Therefore, development of ERK-specific inhibitors carries the promise to effectively abrogate this pathway. Ulixertinib (or BVD-523) is a first-in-class ERK-specific inhibitor that has demonstrated promising antitumor activity in a phase I clinical trial for advanced solid tumors with NRAS and BRAF mutations, providing a strong rationale to test this inhibitor in PDAC. In this study, we show that ulixertinib effectively inhibits in vitro growth of multiple PDAC lines and potentiates the cytotoxic effect of gemcitabine. Moreover, we found that PDAC cells treated with ulixertinib upregulates the parallel PI3K-AKT pathway through activating the HER/ErbB family proteins. Concurrent inhibition of PI3K or HER proteins synergizes with ulixertinib in suppressing PDAC cell growth in vitro and in vivo. Overall, our study provides the preclinical rationale for testing combinations of ulixertinib with chemotherapy or PI3K and HER inhibitors in PDAC patients.
UR - http://www.scopus.com/inward/record.url?scp=85054080980&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-17-1142
DO - 10.1158/1535-7163.MCT-17-1142
M3 - Article
C2 - 30065098
AN - SCOPUS:85054080980
VL - 17
SP - 2144
EP - 2155
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
SN - 1535-7163
IS - 10
ER -