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Review
. 2024 Dec 11;12(4):e2403936.
doi: 10.1002/advs.202403936. Online ahead of print.

Epitranscriptomic RNA m6A Modification in Cancer Therapy Resistance: Challenges and Unrealized Opportunities

Mohammad Burhan Uddin  1 , Zhishan Wang  2 , Chengfeng Yang  2   3
Affiliations
Review

Epitranscriptomic RNA m6A Modification in Cancer Therapy Resistance: Challenges and Unrealized Opportunities

Mohammad Burhan Uddin et al. Adv Sci (Weinh). .

Abstract

Significant advances in the development of new cancer therapies have given rise to multiple novel therapeutic options in chemotherapy, radiotherapy, immunotherapy, and targeted therapies. Although the development of resistance is often reported along with temporary disease remission, there is often tumor recurrence of an even more aggressive nature. Resistance to currently available anticancer drugs results in poor overall and disease-free survival rates for cancer patients. There are multiple mechanisms through which tumor cells develop resistance to therapeutic agents. To date, efforts to overcome resistance have only achieved limited success. Epitranscriptomics, especially related to m6A RNA modification dysregulation in cancer, is an emerging mechanism for cancer therapy resistance. Here, recent studies regarding the contributions of m6A modification and its regulatory proteins to the development of resistance to different cancer therapies are comprehensively reviewed. The promise and potential limitations of targeting these entities to overcome resistance to various anticancer therapies are also discussed.

Keywords: cancer stem cell; cancer therapy resistance; epitranscriptomics; m6A modification; m6A regulator inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
m6A modification regulators (Writers, Erasers, and Readers) and their roles in RNA fate determination. MTC: Methyltransferase complex; Writers (METTL3, METTL14, WTAP, RBM15, RBM15B, VIRMA/KIAA1429, HAKAI, ZC3H13, METTL16); Erasers (FTO, ALKBH5); Readers (YTHDF1‐3, YTHDC1‐2, hnRNPC, hnRNPA2B1, eIF3, IGF2BP1‐3, ELAVL1/HuR, FMRP).
Figure 2
Figure 2
Phenotypic changes in cancer cells associated with m6A RNA modification. Abnormal m6A levels in the RNA transcripts due to aberrant expression of m6A regulators are responsible for cancer cell dedifferentiation, loss/gain‐of‐function, invasiveness, and cancer stem cell (CSC) generation.
Figure 3
Figure 3
Molecular mechanism of m6A modification‐mediated multidrug resistance in cancer cells. Abnormal expressions of m6A regulators alter the m6A landscape in the target transcripts, expressing molecules that are associated with drug transport inside the cells, metabolic processes, programmed cell death, autophagy, DNA damage repair, protumorigenic cellular signaling or immune infiltration in the TME which confer resistance to various therapeutic agents. TME: Tumor microenvironment.
Figure 4
Figure 4
m6A RNA modification is associated with resistance development against conventional cancer therapeutic options. Specific inhibitors developed against different m6A regulators (writers, erasers or readers) could be a promising approach to overcoming resistance to cancer therapeutics.
See this image and copyright information in PMC

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