Abstract 4027: Dual MEK and AKT inhibition suppresses pancreatic cancer growth and migration

Abstract

Pancreatic cancer is one of the deadliest cancers, due to late diagnosis and very few available therapeutic treatments. The Kras gene is frequently mutated in pancreatic cancer, but previous clinical trials using RAS inhibitors have proven ineffective. Additionally, many drug treatments targeting the MAPK pathway have shown little success due to the inherent drug resistance of pancreatic cancer cells and to acquired resistance through activation of alternative proliferative pathways such as JAK-STAT and PI3K-AKT. Our pathway analysis after MEK inhibition in pancreatic cancer cells displayed sustained and/or upregulation of AKT activity in multiple cell lines. Therefore, we hypothesize that a combination treatment of Trametinib and Omipalisib would block two prominent mitogenic pathways (MEK and AKT, respectively) to suppress cancer cell proliferation and migration. Multiple analyses including Western blot, clonogenic, 5-Ethynyl-2’-Deoxyuridine (EDU), and scratch migration assays were employed to determine the augmentation of cellular function in murine and anthropic pancreatic cancer cell lines after single or combination treatment with Trametinib and/or Omipalisib. Results demonstrated that application of Omipalisib alone was successful at blocking pAKT but failed to suppress pERK. Conversely, Trametinib alone selectively inhibited pERK but did not affect pAKT levels. The combination treatment successfully suppressed both pathways in relatively low quantities, indicating their efficacy as a dual therapeutic. Dual therapy was further effective at inhibiting cell growth as evidenced by clonogenic and EdU assays. Recovery and closure from an in vitro scratch wound was also significantly inhibited with combination of Omipalisib and Trametinib. In vivo studies demonstrated that both the pancreatic xenograft mean tumor growth and final tumor size were significantly reduced in response to the combination treatment compared to vehicle. In conclusion, dual therapy with Omipalisib and Trametinib showed a greater anti-tumor efficacy than treatment with either drug alone. Currently, we are determining the prolonged effectiveness of this combination treatment program in genetically-engineered mouse models. If successful, a pharmacological application of Omipalisib and Trametinib has the potential to provide a beneficial therapeutic option to pancreatic cancer patients. Citation Format: Jarrid Jack, Alexandra Pierce, Bailey Bye, McKinnon Walsh, Prabhakar Chalise, Michael N. VanSaun. Dual MEK and AKT inhibition suppresses pancreatic cancer growth and migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4027.

Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects

“…Omipalisib (GSK458, GSk212458) is an ATP-competitive dual PI3K/AKT/mTOR inhibitor proven to be effective in association with trametinib when tested on pancreatic cell lines, demonstrating antitumor activity [ 237 ]. In the first-in-human clinical trial 170 patients (two of which were diagnosed with pancreatic cancer) were enrolled.…”

Clinical and Preclinical Targeting of Oncogenic Pathways in PDAC: Targeted Therapeutic Approaches for the Deadliest Cancer

“…Omipalisib (PI3K/Akt/mTOR inhibitor) together with Trametinib has shown good results in Pancreatic cancer cells recently. The safety study concluded that Omipalisib is tolerable and therefore shows promise for phase II study [ 93 , 94 ]. Two dual inhibitors of PI3K/mTOR namely PF4691502 and Gedatolisib were administered to patients in phase I study with PDAC patients showing no significant improvement [ 95 ].…”