Yutuan Wu1, Jie Huang1, Cristina Ivan2, Yunjie Sun1, Shaolin Ma1, Lingegowda S Mangala1, Bryan M Fellman3, Diana L Urbauer3, Nicholas B Jennings1, Prahlad Ram4, Robert L Coleman1, Wei Hu5, Anil K Sood6. 1. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. 2. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. 3. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. 4. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. 5. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. Electronic address: weihu@mdanderson.org. 6. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. Electronic address: asood@mdanderson.org.
Abstract
BACKGROUND: Our pilot clinical study of EphA2 inhibitor (dasatinib) plus paclitaxel and carboplatin showed interesting clinical activity in endometrial cancer with manageable toxicity. However, the underlying mechanisms of dasatinib resistance in uterine cancer are unknown. Here, we investigated potential mechanisms underlying resistance to EphA2 inhibitors in uterine cancer and examined the anti-tumor activity of EphA2 inhibitors alone and in combination with a MEK inhibitor. METHODS: We evaluated the antitumor activity of EphA2 inhibitors plus a MEK inhibitor using in vitro and in vivo orthotopic models of uterine cancer. RESULTS: EphA2 inhibitor induced MAPK in dasatinib-resistant uterine cancer cells (HEC-1A and Ishikawa) and BRAF/CRAF heterodimerization in HEC-1A cells. EphA2 inhibitor and trametinib significantly increased apoptosis in cancer cells resistant to EphA2 inhibitors compared with controls (p < 0.01). An in vivo study with the orthotopic HEC-1A model showed significantly greater antitumor response to combination treatment compared with dasatinib alone (p < 0.01). Combination treatment increased EphrinA1 and BIM along with decreased pMAPK, Jagged 1, and c-MYC expression in dasatinib-resistant cells. In addition, Spearman analysis using the TCGA data revealed that upregulation of EphA2 was significantly correlated with JAG1, MYC, NOTCH1, NOTCH3 and HES1 expression (p < 0.001, r = 0.25-0.43). Specifically, MAP3K15 and the NOTCH family genes were significantly related to poor clinical outcome in patients with uterine cancer. CONCLUSIONS: These findings indicate that the MAPK pathway is activated in dasatinib-resistant uterine cancer cells and that EphrinA1-mediated MEK inhibition overcomes dasatinib resistance. Dual targeting of both EphA2 and MEK, combined with chemotherapy, should be considered for future clinical development.
BACKGROUND: Our pilot clinical study of EphA2 inhibitor (dasatinib) plus paclitaxel and carboplatin showed interesting clinical activity in endometrial cancer with manageable toxicity. However, the underlying mechanisms of dasatinib resistance in uterine cancer are unknown. Here, we investigated potential mechanisms underlying resistance to EphA2 inhibitors in uterine cancer and examined the anti-tumor activity of EphA2 inhibitors alone and in combination with a MEK inhibitor. METHODS: We evaluated the antitumor activity of EphA2 inhibitors plus a MEK inhibitor using in vitro and in vivo orthotopic models of uterine cancer. RESULTS: EphA2 inhibitor induced MAPK in dasatinib-resistant uterine cancer cells (HEC-1A and Ishikawa) and BRAF/CRAF heterodimerization in HEC-1A cells. EphA2 inhibitor and trametinib significantly increased apoptosis in cancer cells resistant to EphA2 inhibitors compared with controls (p < 0.01). An in vivo study with the orthotopic HEC-1A model showed significantly greater antitumor response to combination treatment compared with dasatinib alone (p < 0.01). Combination treatment increased EphrinA1 and BIM along with decreased pMAPK, Jagged 1, and c-MYC expression in dasatinib-resistant cells. In addition, Spearman analysis using the TCGA data revealed that upregulation of EphA2 was significantly correlated with JAG1, MYC, NOTCH1, NOTCH3 and HES1 expression (p < 0.001, r = 0.25-0.43). Specifically, MAP3K15 and the NOTCH family genes were significantly related to poor clinical outcome in patients with uterine cancer. CONCLUSIONS: These findings indicate that the MAPK pathway is activated in dasatinib-resistant uterine cancer cells and that EphrinA1-mediated MEK inhibition overcomes dasatinib resistance. Dual targeting of both EphA2 and MEK, combined with chemotherapy, should be considered for future clinical development.
Authors: Katherine R Amato; Shan Wang; Andrew K Hastings; Victoria M Youngblood; Pranav R Santapuram; Haiying Chen; Justin M Cates; Daniel C Colvin; Fei Ye; Dana M Brantley-Sieders; Rebecca S Cook; Li Tan; Nathanael S Gray; Jin Chen Journal: J Clin Invest Date: 2014-04-08 Impact factor: 14.808
Authors: Bryan T Hennessy; Yiling Lu; Ana Maria Gonzalez-Angulo; Mark S Carey; Simen Myhre; Zhenlin Ju; Michael A Davies; Wenbin Liu; Kevin Coombes; Funda Meric-Bernstam; Isabelle Bedrosian; Mollianne McGahren; Roshan Agarwal; Fan Zhang; Jens Overgaard; Jan Alsner; Richard M Neve; Wen-Lin Kuo; Joe W Gray; Anne-Lise Borresen-Dale; Gordon B Mills Journal: Clin Proteomics Date: 2010-12 Impact factor: 3.988
Authors: H Miao; B R Wei; D M Peehl; Q Li; T Alexandrou; J R Schelling; J S Rhim; J R Sedor; E Burnett; B Wang Journal: Nat Cell Biol Date: 2001-05 Impact factor: 28.824
Authors: Katherine R Amato; Shan Wang; Li Tan; Andrew K Hastings; Wenqiang Song; Christine M Lovly; Catherine B Meador; Fei Ye; Pengcheng Lu; Justin M Balko; Daniel C Colvin; Justin M Cates; William Pao; Nathanael S Gray; Jin Chen Journal: Cancer Res Date: 2016-01-07 Impact factor: 12.701
Authors: Wei Hu; Tao Liu; Cristina Ivan; Yunjie Sun; Jie Huang; Lingegowda S Mangala; Takahito Miyake; Heather J Dalton; Sunila Pradeep; Rajesh Rupaimoole; Rebecca A Previs; Hee Dong Han; Justin Bottsford-Miller; Behrouz Zand; Yu Kang; Chad V Pecot; Alpa M Nick; Sherry Y Wu; Ju-Seog Lee; Vasudha Sehgal; Prahlad Ram; Jinsong Liu; Susan L Tucker; Gabriel Lopez-Berestein; Keith A Baggerly; Robert L Coleman; Anil K Sood Journal: Cancer Res Date: 2014-04-17 Impact factor: 12.701