Abstract LB-254: Combined inhibition of MEK and autophagy promotes regression of pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a recalcitrant disease responsible for ~43,000 deaths in the USA in 2017. Despite an advanced understanding of the genetics, biochemistry and biology of pancreatic cancer, there is no effective pathway-targeted therapy for PDAC such that the standard of care treatment for most patients remains conventional cytotoxic chemotherapy. Although the clinical picture remains grim, progress has been made in understanding how alterations in tumor suppressors and proto-oncogenes contribute to PDAC initiation and progression. Whereas initiating mutations in KRAS promote the growth of premalignant pancreatic intra-epithelial neoplasia, progression to cancer malignancy requires cooperating alterations of tumor suppressors such as TP53, CDKN2A, and/or SMAD4. Downstream of KRAS oncoproteins, the RAF→MEK→ERK MAP kinase signaling pathway plays a central role in the genesis and maintenance of PDAC. However, to date, pharmacological inhibition of this pathway has demonstrated little clinical benefit in PDAC patients. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling in PDAC cell lines elicits autophagy, a process of cellular self-consumption, which protects pancreatic cancer cells from the potentially cytotoxic effects of pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of ULK1 through the LKB1-AMPK-ULK1 axis. Combined inhibition of MEK1/2 and autophagy (with chloroquine) displays synergistic anti-proliferative effects against PDAC cell lines in vitro. Most strikingly, whereas single agent therapy had modest effects, combined treatment of xenografted patient-derived PDAC tumors with trametinib plus chloroquine/hydroxychloroquine elicited striking tumor regression. Finally, the observed anti-tumor effects of combination trametinib plus chloroquine were observed against a NRAS mutated melanoma and a BRAF mutated colorectal patient-derived xenografts. These data may warrant testing this combination therapy in patients with KRAS mutated pancreatic cancers, a disease for which new pathway-targeted therapies are urgently required. Citation Format: Conan Kinsey, Katrin Guillen, Soledad Camolotto, Amelie Boespflug, Jill Shea, Michael Seipp, Courtney Scaife, Martin McMahon. Combined inhibition of MEK and autophagy promotes regression of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-254.