Inhibition of MEIS3 Generates Cetuximab Resistance through c-Met and Akt

Abstract

Introduction. Although cetuximab has been widely used in the treatment of colon cancer, a large number of patients eventually develop drug resistance. Therefore, it is essential to clarify the mechanism of drug resistance. Methods. In this study, we combined in silico analysis and a single guide RNA (sgRNA) library to locate cetuximab-sensitive genes. Cell proliferation, apoptosis, and cell cycle were assessed to validate the change in cetuximab sensitivity. Finally, western blotting was performed to detect changes in epidermal growth factor (EGFR) upstream and downstream genes. Results. Using in silico analysis and the sgRNA library, MEIS3 was confirmed as the cetuximab-sensitive gene. Further experiments indicated that the expression of MEIS3 could determine the level of cetuximab. Meanwhile, MEIS3-inhibited cells were sensitive to mesenchymal epithelial transition factor (c-Met) and protein kinase B (Akt) inhibitors, which is related to the change in phosphorylation of c-Met and degradation of Akt. Conclusion. MEIS3 modified the sensitivity to cetuximab through c-Met and Akt.

Involvement of Met receptor pathway in aggressive behavior of colorectal cancer cells induced by parathyroid hormone-related peptide

“…Several studies have demonstrated the participation of the Met signaling pathway in the evolution of different types of cancer[ 28 , 33 - 35 , 83 ]. Moreover, this receptor is overexpressed and/or can be aberrantly activated by several mechanisms in CRC cells, triggering tumor development and progression[ 28 , 36 , 38 , 59 ]. A recent study addresses the relationship between the HGF/Met axis and cytokines such as PTHrP in bone metastasis and renal cell cancer progression[ 86 ].…”

“…Met overexpression or its dysregulation can lead to malignant cell transformation and contributes to the development and progression of different types of cancer including colorectal tumors[ 28 , 32 - 35 ]. Moreover, Met dysregulation is also associated with drug resistance in colon cancer cells[ 32 , 35 , 36 ]. Several studies demonstrated the overexpression of this RTK in tumor tissue of CRC patients; in this regard, its inhibition is being widely investigated as a complementary treatment to usual therapies[ 37 , 38 ].…”

A Transcription Factor Signature Can Identify the CMS4 Subtype and Stratify the Prognostic Risk of Colorectal Cancer

“…It was reported that MEIS2 promotes cell migration and invasion in CRC ( 27 ). And MEIS3 can modify the sensitivity to cetuximab via c-Met and Akt ( 28 ). Overexpression of SNAI1 sustains stemness maintenance and promotes invasion in numerous cancers, including CRC ( 29 , 30 ).…”

Colorectal cancer associated with parathyroid hormone-related protein (review)

“…Тот факт, что ПТГрП и его рецептор PTHR1 были обнаружены в нормальном и толстокишечном эпителии [32], ясно указывает на то, что ПТГрП является фактором, который действует как локальный регулятор посредством паракринного/аутокринного пути [33]. Эти исследования вместе с другими, проведенными in vitro [34], предоставили информацию о том, как [62]. Несколько исследований продемонстрировали сверхэкспрессию этого рецептора в опухолевой ткани пациентов с КРР.…”