TY - JOUR
T1 - Bilateral blockade of MEK- and PI3K-mediated pathways downstream of mutant KRAS as a treatment approach for peritoneal mucinous malignancies
AU - Kuracha, Murali R.
AU - Thomas, Peter
AU - Loggie, Brian W.
AU - Govindarajan, Venkatesh
N1 - Funding Information:
These studies were supported by revenue from Nebraska?s excise tax on cigarettes awarded to Creighton University through the Nebraska Department of Health & Human Services (DHHS). Its contents represent the views of the authors and do not necessarily represent the official views of the State of Nebraska or DHHS. This research was supported by National Organization of Rare Disorders (NORD) (VG), LB595 Cancer Development grant (VG), G20RR024001 (Creighton University) and Creighton University patient cancer research funds (BWL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Drs. Thomas Westbrook (Baylor College of Medicine, Houston, TX) for providing the pINDUCER vectors, John Mariadason (Ludwig Cancer Institute, Melbourne, Australia) and Diego Arango (Vall d?Hebron Hospital Research Institute, Barcelona, Spain) for providing the RW7213 and RW2982 cell lines, Genentech for providing Cobimetinib and Pictilisib.
Publisher Copyright:
© 2017 Kuracha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2017/6
Y1 - 2017/6
N2 - Mucinous colorectal adenocarcinomas (MCAs) are clinically and morphologically distinct from nonmucinous colorectal cancers (CRCs), show a distinct spectrum of genetic alterations (higher KRAS mutations, lower p53, high MUC2), exhibit more aggressive behavior (more prone to peritoneal dissemination and lymph node involvement) and are associated with poorer response to chemotherapy with limited treatment options. Here, we report the effectiveness of combinatorial targeting of two KRAS-mediated parallel pathways in reducing MUC2 production and mucinous tumor growth in vitro and in vivo. By knockdown of mutant KRAS we show that, mutant KRAS (a) is necessary for MUC2 production in vitro and (b) synergistically engages PI3K/AKT and MEK/ERK pathways to maintain MUC2 expression in MCA cells. These results define a novel and a previously undescribed role for oncogenic KRAS in mucinous cancers. MCA cells were sensitive to MEK inhibition suggesting cellular dependence (‘addiction’) of KRAS-mutant MCA cells on hyperactivation of the MEK-driven pathway. Interestingly, MCA cells, though initially sensitive, were later resistant to PI3K single agent inhibition. Our studies suggest that this resistance involves dynamic rewiring of signaling circuits mediated through relief of RTK inhibition and MEK-ERK rebound activation. This resistance however, could be overcome by co-targeting of PI3K and MEK. Our studies thus provide a rational basis for MEK- and PI3K-targeted combination therapy for not only KRAS mutant MCA but also for other related mucinous neoplasms that overproduce MUC2 and have a high rate of KRAS mutations such as pseudomyxoma peritonei.
AB - Mucinous colorectal adenocarcinomas (MCAs) are clinically and morphologically distinct from nonmucinous colorectal cancers (CRCs), show a distinct spectrum of genetic alterations (higher KRAS mutations, lower p53, high MUC2), exhibit more aggressive behavior (more prone to peritoneal dissemination and lymph node involvement) and are associated with poorer response to chemotherapy with limited treatment options. Here, we report the effectiveness of combinatorial targeting of two KRAS-mediated parallel pathways in reducing MUC2 production and mucinous tumor growth in vitro and in vivo. By knockdown of mutant KRAS we show that, mutant KRAS (a) is necessary for MUC2 production in vitro and (b) synergistically engages PI3K/AKT and MEK/ERK pathways to maintain MUC2 expression in MCA cells. These results define a novel and a previously undescribed role for oncogenic KRAS in mucinous cancers. MCA cells were sensitive to MEK inhibition suggesting cellular dependence (‘addiction’) of KRAS-mutant MCA cells on hyperactivation of the MEK-driven pathway. Interestingly, MCA cells, though initially sensitive, were later resistant to PI3K single agent inhibition. Our studies suggest that this resistance involves dynamic rewiring of signaling circuits mediated through relief of RTK inhibition and MEK-ERK rebound activation. This resistance however, could be overcome by co-targeting of PI3K and MEK. Our studies thus provide a rational basis for MEK- and PI3K-targeted combination therapy for not only KRAS mutant MCA but also for other related mucinous neoplasms that overproduce MUC2 and have a high rate of KRAS mutations such as pseudomyxoma peritonei.
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U2 - 10.1371/journal.pone.0179510
DO - 10.1371/journal.pone.0179510
M3 - Article
C2 - 28640835
AN - SCOPUS:85021296366
VL - 12
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 6
M1 - e0179510
ER -