CPS1 Promotes Tumor Growth in KRAS/LKB1-Mutant NSCLC

In patients with non–small cell lung cancer (NSCLC) oncogenic mutations in KRAS can occur concurrently with loss of the tumor suppressor LKB1 (encoded by STK11), leading to altered tumor metabolism and aggressive tumors. To identify metabolic vulnerabilities in these KRAS/LKB1-mutant tumors, Kim and colleagues compared the metabolome of NSCLC cells with mutant KRAS to those with mutant KRAS and LKB1 loss. The two cell types were differentiated by differences in nitrogen metabolism; the KRAS/LKB1-mutant cells accumulated several urea cycle metabolites and exhibited increased expression of carbamoyl phosphate synthetase-1 (CPS1), a urea cycle enzyme that produces carbamoyl phosphate from ammonia and bicarbonate in the mitochondria to initiate nitrogen disposal. In lung cancer cell lines and tissue samples, LKB1 expression was inversely correlated with CPS1 expression, and high expression of CPS1 was associated with a poor prognosis in patients with NSCLC. LKB1 reduced CPS1 expression through activation of the fuel sensor AMPK, but a kinase-dead LKB1 mutant did not. CPS1 depletion reduced the viability of KRAS/LKB1-mutant cells, but not KRAS-mutant cells or LKB1-mutant cells, and suppressed colony formation. In vivo, CPS1 depletion suppressed the growth of KRAS/LKB1-mutant xenografts. Mechanistically, CPS1 mediated the transfer of nitrogen from ammonium into the pyrimidine nucleoside thymidine. Thus, CPS1 suppression resulted in pyrimidine depletion and purine accumulation. Disruption of the pyrimidine/purine balance due to CPS1 loss disrupted DNA replication, resulting in DNA polymerase stalling, compromised S-phase progression, and increased DNA damage, and pyrimidine supplementation could rescue the effects of CPS1 depletion. Further, CPS1 depletion combined with treatment with the DNA-damaging agent cisplatin reduced the growth of KRAS/LKB1-mutant tumors in vivo more than CPS1 depletion or cisplatin alone. Altogether, these findings indicate that CPS1 is required to maintain the pyrimidine/purine balance in KRAS/LKB1-mutant cells to prevent DNA damage, and suggest that components of the CPS1 pathway may be therapeutic targets in patients with KRAS/LKB1-mutant NSCLC.

Kim J, Hu Z, Cai L, Li K, Choi E, Faubert B, et al. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature 2017;546:168–72.