N 6 -methyladenosine mRNA methylation of PIK3CB regulates AKT signalling to promote PTEN-deficient pancreatic cancer progression

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Thus far, most drugs have failed to significantly improve patient survival. N -methyladenosine (m A) plays an important role in the progression of PDAC, but its aberrant regulation driven by germline variants in human diseases remains unclear. We first performed an exome-wide association analysis in 518 PDAC patients with overall survival and replicated in an independent population containing 552 PDAC patients. Then, a series of biochemical experiments in vitro and in vivo were conducted to investigate potential mechanisms of the candidate variant and its target gene underlying the PDAC progression. Moreover, the PIK3CB-selective inhibitor KIN-193 was used to block PDAC tumour growth. We identified a missense variant rs142933486 in that is significantly associated with the overall survival of PDAC by reducing the m A level, which facilitated its mRNA and protein expression levels mediated by the m A 'writer' complex (METTL13/METTL14/WTAP) and the m A 'reader' YTHDF2. The upregulation of is widely found in PDAC tumour tissues and significantly correlated with the poor prognosis of PDAC, especially in PTEN-deficient patients. We further demonstrated that overexpression substantially enhanced the proliferation and migration abilities of PTEN-deficient PDAC cells and activated AKT signalling pathway. Remarkably, KIN-193, a PIK3CB-selective inhibitor, is shown to serve as an effective anticancer agent for blocking PTEN-deficient PDAC. These findings demonstrate aberrant m A homoeostasis as an oncogenic mechanism in PDAC and highlight the potential of as a therapeutic target for this disease.