De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression.

Autor:	Tangudu NK; Department of Pharmacology and Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Buj R; Department of Pharmacology and Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Wang H; Department of Pharmacology and Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Wang J; Department of Biomedical Informatics and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Cole AR; Department of Pharmacology and Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Uboveja A; Department of Pharmacology and Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Fang R; Department of Pharmacology and Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Amalric A; Department of Pharmacology and Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Yang B; Department of Pharmacology and Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Tsinghua University School of Medicine, Beijing, P.R. China., Chatoff A; Department of Cardiovascular Sciences, Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania., Crispim CV; Department of Cardiovascular Sciences, Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania., Sajjakulnukit P; Department of Molecular and Integrative Physiology, Department of Internal Medicine, Division of Gastroenterology, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Lyons MA; Genomics Facility, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Cooper K; Biostatistics Facility, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania., Hempel N; Division of Hematology/Oncology, Department of Medicine, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania., Lyssiotis CA; Department of Molecular and Integrative Physiology, Department of Internal Medicine, Division of Gastroenterology, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Chandran UR; Department of Biomedical Informatics and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Snyder NW; Department of Cardiovascular Sciences, Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania., Aird KM; Department of Pharmacology and Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 May 02; Vol. 4 (5), pp. 1174-1188.
DOI:	10.1158/2767-9764.CRC-23-0450
Abstrakt:	p16 is a tumor suppressor encoded by the CDKN2A gene whose expression is lost in approximately 50% of all human cancers. In its canonical role, p16 inhibits the G1-S-phase cell cycle progression through suppression of cyclin-dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. However, the broader impact of p16/CDKN2A loss on other nucleotide metabolic pathways and potential therapeutic targets remains unexplored. Using CRISPR knockout libraries in isogenic human and mouse melanoma cell lines, we determined several nucleotide metabolism genes essential for the survival of cells with loss of p16/CDKN2A. Consistently, many of these genes are upregulated in melanoma cells with p16 knockdown or endogenously low CDKN2A expression. We determined that cells with low p16/CDKN2A expression are sensitive to multiple inhibitors of de novo purine synthesis, including antifolates. Finally, tumors with p16 knockdown were more sensitive to the antifolate methotrexate in vivo than control tumors. Together, our data provide evidence to reevaluate the utility of these drugs in patients with p16/CDKN2Alow tumors as loss of p16/CDKN2A may provide a therapeutic window for these agents. Significance: Antimetabolites were the first chemotherapies, yet many have failed in the clinic due to toxicity and poor patient selection. Our data suggest that p16 loss provides a therapeutic window to kill cancer cells with widely-used antifolates with relatively little toxicity. (© 2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu