TTP enhances the sensitivity of KRASG12C-mutated lung cancer cells to KRASG12C inhibitors by downregulating SLC7A11 and promoting ferroptosis.

Covalent KRASG12C inhibitors are used to treat patients with KRASG12C-mutated non-small cell lung cancer (NSCLC). However, many patients do not respond to therapy due to intrinsic or acquired resistance. The mechanisms underlying resistance to KRASG12C inhibitors are still under investigation. Here, we demonstrate that tristetraprolin (TTP) is a key determinant of intrinsic resistance to KRASG12C inhibitors in NSCLC cells. KRASG12C inhibitors induced ferroptosis in KRASG12C-mutated NSCLC cells, and intrinsic resistance was associated with increased expression of SLC7A11, a crucial regulator of ferroptosis. Compared with sensitive cells, resistant NSCLC cells exhibited greater stability of SLC7A11 mRNA. SLC7A11 mRNA contains an AU-rich element (ARE) within its 3'UTR, and TTP interacts with this ARE to promote mRNA degradation. Silencing TTP in sensitive cells increased SLC7A11 levels, reduced ferroptosis, and enhanced resistance to KRASG12C inhibitors. Conversely, overexpressing TTP in resistant cells decreased SLC7A11 levels, increased ferroptosis, and enhanced sensitivity to KRASG12C inhibitors. Expression of SLC7A11 lacking its 3'UTR abolished the effect of TTP overexpression on ferroptosis. Overall, our findings identify TTP as a key determinant of intrinsic resistance to KRASG12C inhibitors in NSCLC cells through regulation of SLC7A11 mRNA decay, thereby advancing our understanding of the mechanisms underlying intrinsic resistance to KRASG12C inhibitors.