Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis

• Published in: Nature communications Vol. 9; no. 1; pp. 4945 - 13
• Main Authors: Santana-Codina, Naiara, Roeth, Anjali A., Zhang, Yi, Yang, Annan, Mashadova, Oksana, Asara, John M., Wang, Xiaoxu, Bronson, Roderick T., Lyssiotis, Costas A., Ying, Haoqiang, Kimmelman, Alec C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.11.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/109; 13/2; 13/31; 13/51; 13/89; 13/95; 631/45/320; 631/67/1504; 631/67/1504/1713; 631/67/2327; 631/67/395; 82/58; 96/63; Adenocarcinoma; Animals; Biosynthesis; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Dependence; Female; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; K-Ras protein; MAP kinase; MAP Kinase Signaling System - drug effects; MEK inhibitors; Metabolism; Mice; Mice, Nude; multidisciplinary; Myc protein; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pentose; Pentose phosphate pathway; Pentose Phosphate Pathway - drug effects; Protein Kinase Inhibitors - administration & dosage; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Pyrimidines - biosynthesis; Science; Science (multidisciplinary); Signal transduction; Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07472-8

Oncogenic KRAS is the key driver of pancreatic ductal adenocarcinoma (PDAC). We previously described a role for KRAS in PDAC tumor maintenance through rewiring of cellular metabolism to support proliferation. Understanding the details of this metabolic reprogramming in human PDAC may provide novel therapeutic opportunities. Here we show that the dependence on oncogenic KRAS correlates with specific metabolic profiles that involve maintenance of nucleotide pools as key mediators of KRAS-dependence. KRAS promotes these effects by activating a MAPK-dependent signaling pathway leading to MYC upregulation and transcription of the non-oxidative pentose phosphate pathway (PPP) gene RPIA, which results in nucleotide biosynthesis. The use of MEK inhibitors recapitulates the KRAS-dependence pattern and the expected metabolic changes. Antagonizing the PPP or pyrimidine biosynthesis inhibits the growth of KRAS-resistant cells. Together, these data reveal differential metabolic rewiring between KRAS-resistant and sensitive cells, and demonstrate that targeting nucleotide metabolism can overcome resistance to KRAS/MEK inhibition. Pancreatic ductal adenocarcinoma (PDAC) cells display varying degrees of reliance on oncogenic KRAS. Here the authors show that KRAS-resistant PDAC cells maintain nucleotides synthesis through a KRAS-independent upregulation of the non-oxidative pentose phosphate pathway gene RPIA and that targeting nucleotide metabolism restore sensitivity to KRAS pathway inhibition.