PTC124 promotes mutation site-dependent readthrough of STK11 nonsense mutations and restores tumor suppressor function.

Nonsense mutations in the tumor suppressor gene STK11 result in loss of tumor-suppressive function, contributing to cancer progression. PTC124 (Ataluren), a small-molecule compound that promotes ribosomal readthrough of premature stop codons, has emerged as a potential strategy to restore protein expression in such contexts. In this study, PTC124 treatment successfully restored detectable STK11 protein expression in cancer cells harboring specific nonsense mutations. Notably, the readthrough efficiency was mutation-dependent, with preferential rescue observed in N-terminal rather than C-terminal STK11 nonsense mutations. Functionally, restoration of STK11 expression led to activation of the AMPK signaling pathway and subsequent suppression of tumor cell growth. Pharmacological inhibition of AMPK attenuated these effects, further supporting that the antitumor activity of PTC124 is mediated through the STK11-AMPK signaling axis. Collectively, these findings highlight the therapeutic potential of nonsense mutation readthrough strategies and suggest that PTC124 may serve as a precision medicine approach for cancers harboring STK11 nonsense mutations.