Abstract
Over 55,000 people in the United States are diagnosed with pancreatic ductal adenocarcinoma (PDAC) yearly, and fewer than 20% of these patients survive a year beyond diagnosis. Chemotherapies are considered or used in nearly every PDAC case, but there is limited understanding of the complex signaling responses underlying resistance to these common treatments. Here, we take an unbiased approach to study protein kinase network changes following chemotherapies in patient-derived xenograft (PDX) models of PDAC to facilitate design of rational drug combinations. Proteomics profiling following chemotherapy regimens reveals that activation of JNK-JUN signaling occurs after 5-fluorouracil plus leucovorin (5-FU + LEU) and FOLFOX (5-FU + LEU plus oxaliplatin [OX]), but not after OX alone or gemcitabine. Cell and tumor growth assays with the irreversible inhibitor JNK-IN-8 and genetic manipulations demonstrate that JNK and JUN each contribute to chemoresistance and cancer cell survival after FOLFOX. Active JNK1 and JUN are specifically implicated in these effects, and synergy with JNK-IN-8 is linked to FOLFOX-mediated JUN activation, cell cycle dysregulation, and DNA damage response. This study highlights the potential for JNK-IN-8 as a biological tool and potential combination therapy with FOLFOX in PDAC and reinforces the need to tailor treatment to functional characteristics of individual tumors.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer deaths in the United States, in part because over 80% of patients are diagnosed at the outset with locally advanced or metastatic disease for which surgical resection is not an option [1, 2]
Chemotherapies and chemotherapy combinations are widely used in the treatment of PDAC and almost all malignancies, but insufficient consideration has been placed on the signaling responses that underlie intrinsic tumor resistance to these treatments
Global changes in the functional kinome between matched pre- and posttreatment tumors were evaluated by multiplexed-kinase inhibitor bead chromatography with mass spectrometry (MIB-MS) kinome profiling, revealing upregulation of the JNK1-JNK2 signaling cascades after treatment with 5-FU and FOLFOX that did not occur after other chemotherapy regimens
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer deaths in the United States, in part because over 80% of patients are diagnosed at the outset with locally advanced or metastatic disease for which surgical resection is not an option [1, 2]. Significant efforts have instead been taken to evaluate combinations of existing chemotherapies as treatment regimens, and several of these combinations have demonstrated improved patient survival over individual agents and have become preferred treatments for PDAC Despite these successes and new combinations under evaluation, functions of specific signaling networks in mediating response and resistance to these treatments remain incompletely understood. While many drug uptake and metabolic mechanisms for resistance to 5-FU and GEM are known [13, 14], there is much less understanding of the signaling pathway changes, especially in the global set of protein kinases (i.e., the “kinome”) that mediate cell response and survival after treatment with these widely used chemotherapy regimens in PDAC [13, 15]. JNK1 and JUN, unlike JNK2, are sufficient to induce further resistance to FOLFOX and abrogate synergy between FOLFOX and JNK-IN-8, establishing the JNK1-JUN pathway as a critical and therapeutically vulnerable mediator of chemotherapy response in PDAC
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