Targeting METTL3 enhances the chemosensitivity of non-small cell lung cancer cells by decreasing ABCC2 expression in an m⁶A-YTHDF1-dependent manner

Abstract

Patients with non-small cell lung cancer (NSCLC) are easily resistant to first-line chemotherapy with paclitaxel (PTX) or carboplatin (CBP). N⁶-methyladenosine (m⁶A) methyltransferase-like 3 (METTL3) has crucial functions in m⁶A modification and tumorigenesis. However, its role in chemoresistance of NSCLC is still elusive. Here, we demonstrated that METTL3 inhibitor STM2457 significantly reduced the IC₅₀ values of PTX or CBP in NSCLC cells, and they showed a synergistic effect. Comparing with monotherapy, a combination of STM2457 and PTX or CBP exhibited more potent <i>in vitro</i> and <i>in vivo</i> anti-tumor efficacy. In addition, we found that ATP binding cassette subfamily C member 2 (ABCC2) was responsively elevated in cytomembrane after PTX or CBP treatment, and targeting METTL3 could reverse this effect. Mechanistically, targeting METTL3 decreased the m⁶A modification of <i>ABCC2</i> mRNA and accelerated its mRNA degradation. Further studies revealed that YTHDF1 could bind and stabilize the m⁶A-modified mRNA of <i>ABCC2</i>, while YTHDF1 knockdown promoted it mRNA degradation. These results, taken together, demonstrate that targeting METTL3 enhances the sensitivity of NSCLC cells to PTX or CBP by decreasing the cytomembrane-localized ABCC2 in an m⁶A-YTHDF1-dependent manner, and suggest that METTL3 may be a potential therapeutic target for acquired resistance to PTX or CBP in NSCLC.