A subset of VEGFR‐TKIs activates AMPK in LKB1‐mutant lung cancer

Abstract

The mutation of tumor suppressor gene liver kinase B1 (LKB1) has a prevalence of about 20% in non–small cell lung cancer (NSCLC). LKB1‐mutant lung cancer is characterized by enhanced aggressiveness and immune escape and is associated with poor prognosis. Therefore, it is urgent to develop effective therapeutic methods for LKB1‐mutant NSCLC. Recently, apatinib, a VEGFR‐TKI, was found to significantly improve the outcome of LKB1‐mutant NSCLC, but the mechanism is not completely clear. In this study, AMP‐activated protein kinase (AMPK), the crucial downstream kinase of LKB1 was excavated as the potential target of apatinib. Biochemical experiments verified that apatinib is a direct AMPK activator. Moreover, clinically available VEGFR‐TKIs were found to regulate AMPK differently: Apatinib and anlotinib can directly activate AMPK, while axitinib and sunitinib can directly inhibit AMPK. Activation of AMPK by apatinib leads to the phosphorylation of acetyl‐CoA carboxylase (ACC) and inhibition of de novo fatty acid synthesis (FAsyn), which is upregulated in LKB1‐null cancers. Moreover, the killing effect of apatinib was obviously enhanced under delipidated condition, and the combination of exogenous FA restriction with apatinib treatment can be a promising method for treating LKB1‐mutant NSCLC. This study discovered AMPK as an important off‐target of apatinib and elucidated different effects of this cluster of VEGFR‐TKIs on AMPK. This finding can be the basis for the accurate and combined application of these drugs in clinic and highlights that the subset of VEGFR‐TKIs including apatinib and anlotinib are potentially valuable in the treatment of LKB1‐mutant NSCLC.