Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal human diseases and remains largely refractory to available drug treatments. Insufficient targeting of the known oncogenic drivers and activation of compensatory feedback loops and inability to prevent metastatic spread contribute to poor prognosis for this disease. The KRAS-driven MEK pathway is mutationally activated in most pancreatic cancers and is an important target for therapeutics. Using a two-dimensional monolayer culture system as well as three-dimensional spheroid culture system, we conducted a screen of a large panel of anticancer agents and found that MAP2K (MEK) inhibitors were most effective in targeting PDAC spheroids in comparison with monolayer cultures. Combination treatment with an MEK inhibitor and the multikinase inhibitor ponatinib was effective in targeting pancreatic cancer cells both in monolayer and spheroids by effectively blocking signaling via the PDGFRα and MEK kinases, while also preventing the activation of STAT3- and S6-mediated compensatory feedback loops in cancer cells. Furthermore, using xenograft models, we demonstrate that cotreatment with a MEK inhibitor and ponatinib causes significant tumor regression. PDAC patient samples also provided evidence of increased STAT3 activation in PDAC tumors and MAPK1 (ERK) activation in liver metastases, implicating STAT3 and ERK as key drivers in primary tumors and metastases, respectively. These results reveal a combination drug treatment strategy that may be effective in pancreatic cancer. Mol Cancer Ther; 16(9); 1729-38. ©2017 AACR.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers, and numerous therapeutic approaches have been explored on the basis of drug response findings from pancreatic cancer cells tested in two-dimensional culture models [1, 2]
Increased sensitivity to MEK inhibition in pancreatic cancer cell spheroid cultures To broadly compare how pancreatic cancer cells cultured in 2D and 3D cultures respond to various cancer therapeutic agents, we treated the KRAS-mutant PDAC cancer cell line KP4 with a panel of 203 small-molecule inhibitors of cancer-relevant targets and known chemotherapeutics (Supplementary Table S1)
Expression of EPHA1 and EPHB1 was selectively elevated in KP4 spheroids upon MEK inhibition (Fig. 1D). These findings reveal a drug response profile specific to 3D culture conditions for PDAC-derived cells that largely depend on the MEK pathway for their growth and survival, without switching to other survival pathways that may contribute to the increased sensitivity to drug treatment relative to that seen in standard 2D conditions
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers, and numerous therapeutic approaches have been explored on the basis of drug response findings from pancreatic cancer cells tested in two-dimensional culture models [1, 2]. Far, these have largely failed to translate successfully to the clinic, potentially due to the insufficient recapitulation of the tumor context in vivo in this simple culture condition. We compared the sensitivity of PDAC cancer cells in 2D and 3D cultures with small-molecule inhibitors in a high-throughput screening (HTS) assay to identify inhibitors that are most effective for targeting pancreatic cancer cells
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