Meng Su1, Lei Zhan1, Yong Zhang2, Jingdong Zhang1. 1. Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China. 2. Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.
Abstract
BACKGROUND: Most colorectal cancer (CRC) patients with the BRAF V600E mutation display resistance to chemotherapy and targeted medicinal treatments. Thus, exploring new drugs and drug resistance mechanisms for the BRAF V600E mutation has become an urgent clinical priority. METHODS: MTS experiment, cell cloning experiment, cell scratching experiment, Transwell experiment, chromatin immunoprecipitation (ChIP), quantitative polymerase chain reaction (qPCR) and flow cytometry are used. Detect the transcription and protein expression of YAP in colorectal cancer cell lines, establish a transient cell line with YAP gene overexpression and knockdown, and detect the effect of YAP gene expression on the biological functions of colorectal cancer cells RKO and HT-29. And further study the mechanism of YAP regulating the response of RAF and MEK targeted therapy. RESULTS: In this study, for the first time, we verified that the expression of transcription factor yes-associated protein (YAP) was upregulated in BRAF V600E mutant CRC cells. After knocking down YAP, we observed a reduction in the growth rate, proliferation, and invasion ability of colon cancer cells. We further verified that YAP knockdown increased sensitivity of BRAF V600E mutant CRC cells to mitogen-activated protein kinase (MAPK) pathway inhibitors. In addition, we clarified the mechanism underlying YAP regulation of RAF and MAPK/extracellular signal-regulated kinase (MEK)-targeted therapy response: YAP cooperates with RAF→MEK pathway inhibitors to regulate the cell cycle, increase cell G1/S phase arrest, and increase apoptosis. CONCLUSIONS: These results suggest that YAP expression may be related to the primary resistance of MAPK inhibitors in metastatic CRC with the BRAF V600E mutation. Therefore, the combination of YAP and MAPK pathway inhibitors in BRAF V600E mutant metastatic CRC may present a promising treatment method. 2021 Journal of Gastrointestinal Oncology. All rights reserved.
BACKGROUND: Most colorectal cancer (CRC) patients with the BRAF V600E mutation display resistance to chemotherapy and targeted medicinal treatments. Thus, exploring new drugs and drug resistance mechanisms for the BRAF V600E mutation has become an urgent clinical priority. METHODS: MTS experiment, cell cloning experiment, cell scratching experiment, Transwell experiment, chromatin immunoprecipitation (ChIP), quantitative polymerase chain reaction (qPCR) and flow cytometry are used. Detect the transcription and protein expression of YAP in colorectal cancer cell lines, establish a transient cell line with YAP gene overexpression and knockdown, and detect the effect of YAP gene expression on the biological functions of colorectal cancer cells RKO and HT-29. And further study the mechanism of YAP regulating the response of RAF and MEK targeted therapy. RESULTS: In this study, for the first time, we verified that the expression of transcription factor yes-associated protein (YAP) was upregulated in BRAF V600E mutant CRC cells. After knocking down YAP, we observed a reduction in the growth rate, proliferation, and invasion ability of colon cancer cells. We further verified that YAP knockdown increased sensitivity of BRAF V600E mutant CRC cells to mitogen-activated protein kinase (MAPK) pathway inhibitors. In addition, we clarified the mechanism underlying YAP regulation of RAF and MAPK/extracellular signal-regulated kinase (MEK)-targeted therapy response: YAP cooperates with RAF→MEK pathway inhibitors to regulate the cell cycle, increase cell G1/S phase arrest, and increase apoptosis. CONCLUSIONS: These results suggest that YAP expression may be related to the primary resistance of MAPK inhibitors in metastatic CRC with the BRAF V600E mutation. Therefore, the combination of YAP and MAPK pathway inhibitors in BRAF V600E mutant metastatic CRC may present a promising treatment method. 2021 Journal of Gastrointestinal Oncology. All rights reserved.
Entities:
Keywords:
BRAF V600E mutation; Colorectal cancer (CRC); mitogen-activated protein kinase pathway (MAPK pathway); yes-activated protein
Authors: Yu Fang Wang; Chen Chen Jiang; Kelly Anne Kiejda; Susan Gillespie; Xu Dong Zhang; Peter Hersey Journal: Clin Cancer Res Date: 2007-07-25 Impact factor: 12.531
Authors: Zhiqiang Li; Pedram Razavi; Qing Li; Weiyi Toy; Bo Liu; Christina Ping; Wilson Hsieh; Francisco Sanchez-Vega; David N Brown; Arnaud F Da Cruz Paula; Luc Morris; Pier Selenica; Emily Eichenberger; Ronglai Shen; Nikolaus Schultz; Neal Rosen; Maurizio Scaltriti; Edi Brogi; Jose Baselga; Jorge S Reis-Filho; Sarat Chandarlapaty Journal: Cancer Cell Date: 2018-12-10 Impact factor: 31.743
Authors: Angela Lauriola; Elisa Uliassi; Matteo Santucci; Maria Laura Bolognesi; Marco Mor; Laura Scalvini; Gian Marco Elisi; Gaia Gozzi; Lorenzo Tagliazucchi; Gaetano Marverti; Stefania Ferrari; Lorena Losi; Domenico D'Arca; Maria Paola Costi Journal: Pharmaceutics Date: 2022-02-10 Impact factor: 6.321