CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells

Abstract

In human cell lines with mutant KRAS and loss of LKB1, CPS1 expression correlates inversely with LKB1 expression; silencing CPS1 in these cells induces DNA damage and cell death as a result of pyrimidine depletion rather than ammonia toxicity. Cancer cells have an altered cellular metabolism to adjust to their metabolic needs for tumour cell proliferation. Ralph DeBerardinis and colleagues now show an unexpected role for the metabolic enzyme CPS1, which normally functions in the urea cycle. They show that, in lung cancer cells, CPS1 expression is increased when the tumour suppressor LKB1 is deleted, and functions to promote pyrimidine synthesis. This is important for supplying nucleotides for DNA synthesis during cancer cell proliferation. The authors suggest that CPS1-related pathways could represent therapeutic targets in lung adenocarcinomas. Metabolic reprogramming by oncogenic signals promotes cancer initiation and progression. The oncogene KRAS and tumour suppressor STK11, which encodes the kinase LKB1, regulate metabolism and are frequently mutated in non-small-cell lung cancer (NSCLC). Concurrent occurrence of oncogenic KRAS and loss of LKB1 (KL) in cells specifies aggressive oncological behaviour1,2. Here we show that human KL cells and tumours share metabolomic signatures of perturbed nitrogen handling. KL cells express the urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1), which produces carbamoyl phosphate in the mitochondria from ammonia and bicarbonate, initiating nitrogen disposal. Transcription of CPS1 is suppressed by LKB1 through AMPK, and CPS1 expression correlates inversely with LKB1 in human NSCLC. Silencing CPS1 in KL cells induces cell death and reduces tumour growth. Notably, cell death results from pyrimidine depletion rather than ammonia toxicity, as CPS1 enables an unconventional pathway of nitrogen flow from ammonia into pyrimidines. CPS1 loss reduces the pyrimidine to purine ratio, compromises S-phase progression and induces DNA-polymerase stalling and DNA damage. Exogenous pyrimidines reverse DNA damage and rescue growth. The data indicate that the KL oncological genotype imposes a metabolic vulnerability related to a dependence on a cross-compartmental pathway of pyrimidine metabolism in an aggressive subset of NSCLC.

Cite this article

Kim, J., Hu, Z., Cai, L. et al. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature 546, 168–172 (2017). https://doi.org/10.1038/nature22359

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