N⁶-methyladenosine mRNA methylation of <i>PIK3CB</i> regulates AKT signalling to promote PTEN-deficient pancreatic cancer progression.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Thus far, most drugs have failed to significantly improve patient survival. N⁶-methyladenosine (m⁶A) 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 <i>PIK3CB</i> 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 <i>PIK3CB</i> that is significantly associated with the overall survival of PDAC by reducing the <i>PIK3CB</i> m⁶A level, which facilitated its mRNA and protein expression levels mediated by the m⁶A 'writer' complex (METTL13/METTL14/WTAP) and the m⁶A 'reader' YTHDF2. The upregulation of <i>PIK3CB</i> 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 <i>PIK3CB</i> 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 m⁶A homoeostasis as an oncogenic mechanism in PDAC and highlight the potential of <i>PIK3CB</i> as a therapeutic target for this disease.