Biological and pharmacological roles of m6A modifications in cancer drug resistance

Abstract

Cancer drug resistance represents the main obstacle in cancer treatment. Drug-resistant cancers exhibit complex molecular mechanisms to hit back therapy under pharmacological pressure. As a reversible epigenetic modification, N6-methyladenosine (m6A) RNA modification was regarded to be the most common epigenetic RNA modification. RNA methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers) are frequently disordered in several tumors, thus regulating the expression of oncoproteins, enhancing tumorigenesis, cancer proliferation, development, and metastasis. The review elucidated the underlying role of m6A in therapy resistance. Alteration of the m6A modification affected drug efficacy by restructuring multidrug efflux transporters, drug-metabolizing enzymes, and anticancer drug targets. Furthermore, the variation resulted in resistance by regulating DNA damage repair, downstream adaptive response (apoptosis, autophagy, and oncogenic bypass signaling), cell stemness, tumor immune microenvironment, and exosomal non-coding RNA. It is highlighted that several small molecules targeting m6A regulators have shown significant potential for overcoming drug resistance in different cancer categories. Further inhibitors and activators of RNA m6A-modified proteins are expected to provide novel anticancer drugs, delivering the therapeutic potential for addressing the challenge of resistance in clinical resistance.

FAM120A deficiency improves resistance to cisplatin in gastric cancer by promoting ferroptosis

“…N6-methyladenosine (m6A) is an important RNA modification that is regulated by methyltransferases, demethylases, and effector proteins 25 . m6A is implicated in tumor formation and development, as well as radiotherapy, chemotherapy, and immunotherapy 26 – 28 . A mounting body of research indicates a close correlation between m6A and the development of chemoresistance in GC.…”

Roles of RNA Methylations in Cancer Progression, Autophagy, and Anticancer Drug Resistance

“…An analysis of the cancer methylome revealed that global methylation patterns could regulate therapeutic resistance [ 126 ]. Alterations of the m6A modifications interferes with drug efficacy by modulating the expression of multidrug efflux transporters (e.g., ABCG2, ABCC9, and ABCC10), drug-metabolizing enzymes (e.g., CYP2C8), and drug targets (e.g., p53 R273H) [ 127 ]. For example, METTL3 confers imatinib resistance, and high levels of METTL3 could predict the poor prognosis of patients with gastrointestinal stromal tumors (GISTs) [ 128 ].…”

The roles and therapeutic implications of messenger RNA internal N7‐methylguanosine and N6‐methyladenosine modifications in chemoresistance

“…Some encouraging results have been achieved for small molecules targeting m 6 A regulators in different cancer types. For example, meclofenamic acid, an FTO inhibitor, restores gefitinib sensitivity in non‐small cell lung cancer, and the combination of rhein (another FTO inhibitor) with tyrosine kinase inhibitors (TKIs) may benefit tyrosine kinase inhibitor‐resistant cancer patients 8 . In terms of m 7 G regulators, while our work highlights the significance of QKIs as internal m 7 G readers in drug resistance, several additional studies underscore the importance of m 7 G writers METTL1/WDR4 in chemoresistance 9 .…”