The N6-methyladenosine (m6A) modification of the multidrug resistance-associated protein 1 (MRP1) mRNA promotes drug resistance in gastrointestinal stromal tumors (GISTs), a new study published in Cancer Letters found. This suggests that MRP1 could be a potential therapeutic target for imatinib-resistant GIST.

GISTs are abnormal mesenchymal cell growths of the gastrointestinal tract. Patients undergo complete surgical resection for the disease, but the disease can also be treated medically in which case imatinib is the first-line treatment. 

However, around half of patients develop resistance to imatinib after 2 years of treatment. Previous research has shown that the mRNA modification m6A may be involved in drug resistance and cancer prognosis, but the role of m6A in imatinib resistance in GIST is not clear.


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Here, a team of researchers from China led by Hao Xu showed that the levels of m6A are elevated in GIST cells and tissues that are resistant to imatinib. They also showed that 1 of the main proteins responsible for this elevation was the methyltransferase-like 3 (METTL3).

The team showed that METTL3 mediated the m6A modification of the MRP1 mRNA, thereby stimulating its translation via binding with the YT521-B homology (YTH) domain family proteins YTHDF1, which increases the efficacy of mRNA translation and the translation elongation factor eEF-1. This ultimately leads to imatinib resistance of GIST, they said.

Finally, the researchers found that the transcription factor ETV1 promoted the transcription of METTL3 and increased METTL3 production in imatinib-resistant GIST cells.

“Increased METTL3 levels contributed to imatinib resistance and worse progression-free survival of GIST patients,” the researchers wrote. They concluded that MRP1 could be a potential therapeutic target for imatinib-resistant GIST. Imatinib administration together with MRP1 inhibition might resensitize patients with GIST to imatinib.

Reference

Xu K, Zhang Q, Chen M, et al. N6-methyladenosine modification regulates imatinib resistance of gastrointestinal stromal tumor by enhancing the expression of multidrug transporter MRP1. Cancer Lett. Published online January 13, 2022. doi:10.1016/j.canlet.2022.01.008