Data from N⁶-methyladenosine Modification of FZR1 mRNA Promotes Gemcitabine Resistance in Pancreatic Cancer

The therapeutic options for treating pancreatic ductal adenocarcinoma (PDAC) are limited, and resistance to gemcitabine, a cornerstone of PDAC chemotherapy regimens, remains a major challenge. N⁶-methyladenosine (m⁶A) is a prevalent modification in mRNA that has been linked to diverse biological processes in human diseases. Herein, by characterizing the global m⁶A profile in a panel of gemcitabine-sensitive and gemcitabine-insensitive PDAC cells, we identified a key role for elevated m⁶A modification of the master G₀–G₁ regulator FZR1 in regulating gemcitabine sensitivity. Targeting FZR1 m⁶A modification augmented the response to gemcitabine treatment in gemcitabine-resistant PDAC cells both in vitro and in vivo. Mechanistically, GEMIN5 was identified as a novel m⁶A mediator that specifically bound to m⁶A-modified FZR1 and recruited the eIF3 translation initiation complex to accelerate FZR1 translation. FZR1 upregulation maintained the G₀–G₁ quiescent state and suppressed gemcitabine sensitivity in PDAC cells. Clinical analysis further demonstrated that both high levels of FZR1 m⁶A modification and FZR1 protein corresponded to poor response to gemcitabine. These findings reveal the critical function of m⁶A modification in regulating gemcitabine sensitivity in PDAC and identify the FZR1–GEMIN5 axis as a potential target to enhance gemcitabine response.

Increased FZR1 translation induced by m⁶A modification engenders a gemcitabine-resistant phenotype by inducing a quiescent state and confers a targetable vulnerability to improve treatment response in PDAC.