c-Met Targeting Enhances the Effect of Irradiation and Chemical Agents against Malignant Colon Cells Harboring a KRAS Mutation

Abstract

Although EGFR-targeted therapy has been beneficial to colorectal cancer patients, several studies have showed this clinical benefit was restricted to patients with wild-type KRAS exon 2 colorectal cancer. Therefore, it is crucial to explore efficient treatment strategies in patients with KRAS mutations. c-Met is an emerging target for the development of therapeutics against colorectal cancer. In this study, we first used the SW620 cell line, which has an activating KRAS mutation, to generate a stable cell line with conditional regulation of c-Met, which is an essential gene for growth and an oncogene. Using this approach, we evaluated the benefits of combined c-Met-targeted therapy with irradiation or chemical agents. In this cell line, we observed that the proliferation and migration of SW620 cells were reduced by the induction of c-Met shRNA. Furthermore, c-Met knockdown enhanced the anti-proliferative effects of 5-FU and Taxol but not cisplatin, irinotecan or sorafenib. These enhancements were also observed in another colon cancer cells line HCT-116, which also has a KRAS mutation. The response of SW620 cells to irradiation was also enhanced by c-Met knockdown. This method and obtained data might have important implications for exploring the combinatory effects of targeted therapies with conventional medications. Moreover, the data suggested that the combination of c-Met-targeted therapy with chemotherapy or irradiation might be an effective strategy against colorectal cancer harboring a KRAS mutation.

Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers

“…MET is highly expressed in ~67% of primary colorectal carcinomas ( Gayyed et al, 2015 ) and overexpression is associated with tumor progression and metastasis ( Baldus et al, 2007 ; Luo and Xu, 2014 ; Zeng et al, 2004 ). MET is necessary for proliferation of colorectal carcinomas ( Li et al, 2014 ), and selective inhibition of MET with small molecule inhibitors is effective in reducing proliferation of HCT116 cells ( Larsen and Dashwood, 2010 ). In HCT116 cells, we identified multiple accessible regions from Clusters 4 and 6 that are co-bound by the AP-1 complex and the SWI/SNF complex within and downstream of the MET gene ( Figure 5F , data not shown).…”

Receptor tyrosine kinase MET as potential target of multi‐kinase inhibitor and radiosensitizer sorafenib in HNSCC

“…With respect to EGFR, we have recently demonstrated that inhibition failed to induce significant cell death or robust radiosensitization in the cell lines used in this study. Although MET inhibition induces radiosensitization in other entities, it also failed to do so in our HNSCC cells pretreated for 2 hours with 2 different MET inhibitors. Additionally, effects of crizotinib or SU11274 on proliferation and cell survival without irradiation turned out to be very limited in the sub‐micromolar range, the concentration range where maximal MET inhibition was already achievable at the protein level (see Figure ).…”

<em>ITGA7 </em>functions as a tumor suppressor and regulates migration and invasion in breast cancer

“…In recent decades, the development of c-met has been increasingly recognized to play pivotal roles in promoting tumor process. 22 – 24 Jia et al 25 found that inhibiting c-MET could enhance the response of the colorectal cancer cells to irradiation in vitro and in vivo. Our study proved that knocking down ITGA7 could enhance c-met.…”