Abstract
Activating mutations in the KRAS oncogene occur in approximately 90% of pancreatic cancers, resulting in aberrant activation of the MAPK and the PI3K pathways, driving malignant progression. Significant efforts to develop targeted inhibitors of nodes within these pathways are underway and several are currently in clinical trials for patients with KRAS-mutant tumors, including patients with pancreatic cancer. To model MEK and PI3K inhibition in late-stage pancreatic cancer, we conducted preclinical trials with a mutant Kras-driven genetically engineered mouse model that faithfully recapitulates human pancreatic ductal adenocarcinoma development. Treatment of advanced disease with either a MEK (GDC-0973) or PI3K inhibitor (GDC-0941) alone showed modest tumor growth inhibition and did not significantly enhance overall survival. However, combination of the two agents resulted in a significant survival advantage as compared with control tumor-bearing mice. To model the clinical scenario, we also evaluated the combination of these targeted agents with gemcitabine, the current standard-of-care chemotherapy for pancreatic cancer. The addition of MEK or PI3K inhibition to gemcitabine, or the triple combination regimen, incrementally enhanced overall survival as compared with gemcitabine alone. These results are reminiscent of the survival advantage conferred in this model and in patients by the combination of gemcitabine and erlotinib, an approved therapeutic regimen for advanced nonresectable pancreatic cancer. Taken together, these data indicate that inhibition of MEK and PI3K alone or in combination with chemotherapy do not confer a dramatic improvement as compared with currently available therapies for patients with pancreatic cancer.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, with the majority of patients suffering from advanced unresectable disease at the time of diagnosis [1]
Tumor models were inoculated as follows: KP4.Â1.1: 5 Â 106 cells were inoculated into Hank balanced salt solution (HBSS)/Matrigel into CRL nu/nu mice; HPAC: 5 Â 106 cells were inoculated into HBSS/Matrigel into CRL nu/nu mice; Panc-1: 1 mm3 Panc-1 tumor chunks were transplanted into HRLN nu/nu mice; MiaPaCa-2: 1 mm3 MiaPaCa-2 tumor chunks were transplanted into HRLN nu/nu mice
We examined the status of MEK and PI3K signaling in latestage tumors in KrasG12D; p16/p19fl/fl; Pdx1-Cre mice via immunohistochemical staining for the downstream markers phosphoERK and phospho-S6, respectively (Fig. 1A)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, with the majority of patients suffering from advanced unresectable disease at the time of diagnosis [1]. MAPK pathway inhibition alone and in combination with chemotherapy showed promising efficacy in a mutant Kras-driven genetically engineered mouse model (GEMM) of non–small cell lung carcinoma (NSCLC) and translated into a positive clinical outcome [6, 7]. Clinical and preclinical results have clearly demonstrated the existence of feedback loops that drive intrinsic and acquired resistance to MAPK pathway inhibitors, often involving activation of the PI3K pathway [8] To overcome these feedback mechanisms, combinatorial therapeutic regimens, including simultaneous MEK and PI3K pathway inhibition have been proposed [9]. These regimens have proven promising in preclinical models including a mutant Kras-driven GEMM of NSCLC, and are currently being tested in the clinical setting [10]. We observed a significant albeit transient effect on tumor growth when these regimens were applied to animals harboring late-stage disease, resulting in increases of overall survival
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