Abstract / Summary
Abstract In patients with non-small cell lung cancer (NSCLC) treated with KRAS G12C inhibitors, co-occurring mutations in STK11 and KEAP1 are associated with earlier disease progression and poor clinical outcomes. However, the mechanisms underlying primary resistance to KRAS G12C inhibitors remain obscure. Here, we show that loss of KEAP1 function makes tumor cells dependent on pyruvate carboxylase (PC) to sustain nucleotide biosynthesis during KRAS G12C inhibitor treatment. KEAP1 deficiency leads to constitutive activation of NRF2, which promotes PC expression. Metabolic profiling and isotope tracing showed that elevated PC activity channels glucose-derived carbon into the TCA cycle and increases oxaloacetate availability. This supports aspartate synthesis and subsequent de novo pyrimidine biosynthesis. Mechanistically, this metabolic rewiring provides the biosynthetic precursors required to maintain nucleotide pools and allows tumor cells to sustain proliferation during KRAS G12C inhibition. Importantly, in models harboring concurrent STK11 and KEAP1 mutations, genetic ablation of PC restored sensitivity to KRAS G12C inhibition and suppressed tumor growth. Our findings identify PC-mediated anaplerosis as a metabolic vulnerability in STK11 and KEAP1 co-mutant tumors and provide a rationale for targeting PC in combination with KRAS G12C inhibition to overcome primary resistance.