Bilateral blockade of MEK- and PI3K-mediated pathways downstream of mutant KRAS as a treatment approach for peritoneal mucinous malignancies

被引:14
作者
Kuracha, Murali R. [1 ]
Thomas, Peter [1 ]
Loggie, Brian W. [1 ]
Govindarajan, Venkatesh [2 ]
机构
[1] Creighton Univ, Dept Surg, Omaha, NE 68178 USA
[2] Creighton Univ, Dept Biomed Sci, Omaha, NE 68178 USA
关键词
COLORECTAL-CANCER; PSEUDOMYXOMA-PERITONEI; TUMOR-GROWTH; IN-VITRO; INHIBITION; CARCINOMA; BRAF; PROGNOSIS; KINASE; MUC2;
D O I
10.1371/journal.pone.0179510
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 MEKdriven 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.
引用
收藏
页数:17
相关论文
共 44 条
[1]   American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS Gene Mutations in Patients With Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy [J].
Allegra, Carmen J. ;
Jessup, J. Milburn ;
Somerfield, Mark R. ;
Hamilton, Stanley R. ;
Hammond, Elizabeth H. ;
Hayes, Daniel F. ;
McAllister, Pamela K. ;
Morton, Roscoe F. ;
Schilsky, Richard L. .
JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (12) :2091-2096
[2]  
Bosman FT, 2010, WHO Classification of tumors of the digestive system, V4th
[3]   Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy [J].
Catalano, V. ;
Loupakis, F. ;
Graziano, F. ;
Torresi, U. ;
Bisonni, R. ;
Mari, D. ;
Fornaro, L. ;
Baldelli, A. M. ;
Giordani, P. ;
Rossi, D. ;
Alessandroni, P. ;
Giustini, L. ;
Silva, R. R. ;
Falcone, A. ;
D'Emidio, S. ;
Fedeli, S. L. .
BRITISH JOURNAL OF CANCER, 2009, 100 (06) :881-887
[4]   MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road [J].
Caunt, Christopher J. ;
Sale, Matthew J. ;
Smith, Paul D. ;
Cook, Simon J. .
NATURE REVIEWS CANCER, 2015, 15 (10) :577-592
[5]   AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity [J].
Chandarlapaty, Sarat ;
Sawai, Ayana ;
Scaltriti, Maurizio ;
Rodrik-Outmezguine, Vanessa ;
Grbovic-Huezo, Olivera ;
Serra, Violeta ;
Majumder, Pradip K. ;
Baselga, Jose ;
Rosen, Neal .
CANCER CELL, 2011, 19 (01) :58-71
[6]   QUANTITATIVE-ANALYSIS OF DOSE-EFFECT RELATIONSHIPS - THE COMBINED EFFECTS OF MULTIPLE-DRUGS OR ENZYME-INHIBITORS [J].
CHOU, TC ;
TALALAY, P .
ADVANCES IN ENZYME REGULATION, 1984, 22 :27-55
[7]   Mucin as a therapeutic target in pseudomyxoma peritonei [J].
Choudry, Haroon A. ;
O'Malley, Mark E. ;
Guo, Zong Sheng ;
Zeh, Herbert J. ;
Bartlett, David L. .
JOURNAL OF SURGICAL ONCOLOGY, 2012, 106 (07) :911-917
[8]   Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer [J].
Corcoran, Ryan B. ;
Atreya, Chloe E. ;
Falchook, Gerald S. ;
Kwak, Eunice L. ;
Ryan, David P. ;
Bendell, Johanna C. ;
Hamid, Omid ;
Messersmith, Wells A. ;
Daud, Adil ;
Kurzrock, Razelle ;
Pierobon, Mariaelena ;
Sun, Peng ;
Cunningham, Elizabeth ;
Little, Shonda ;
Orford, Keith ;
Motwani, Monica ;
Bai, Yuchen ;
Patel, Kiran ;
Venook, Alan P. ;
Kopetz, Scott .
JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (34) :4023-+
[9]   EGFR-Mediated Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF-Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib [J].
Corcoran, Ryan B. ;
Ebi, Hiromichi ;
Turke, Alexa B. ;
Coffee, Erin M. ;
Nishino, Michiya ;
Cogdill, Alexandria P. ;
Brown, Ronald D. ;
Della Pelle, Patricia ;
Dias-Santagata, Dora ;
Hung, Kenneth E. ;
Flaherty, Keith T. ;
Piris, Adriano ;
Wargo, Jennifer A. ;
Settleman, Jeffrey ;
Mino-Kenudson, Mari ;
Engelman, Jeffrey A. .
CANCER DISCOVERY, 2012, 2 (03) :227-235
[10]   Mitogen-activated protein kinase inhibition reduces mucin 2 production and mucinous tumor growth [J].
Dilly, Ashok K. ;
Song, Xinxin ;
Zeh, Herbert J. ;
Guo, Zong S. ;
Lee, Yong J. ;
Bartlett, David L. ;
Choudry, Haroon A. .
TRANSLATIONAL RESEARCH, 2015, 166 (04) :344-354