Abstract 6202: 6-Phosphofructo-2-kinase in regulating DNA damage and repair in EGFR-driven lung cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 83; no. 7_Supplement; p. 6202
• Main Authors: Lypova, Nadiia, Lanceta, Lilibeth, Dougherty, Susan, Chesney, Jason, Imbert-Fernandez, Yoannis
• Format: Journal Article
• Language: English
• Published: 04-04-2023
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-6202

Activating mutations of epidermal growth factor receptor (mutEGFR) are established drivers of lung tumor development, aggressiveness, and resistance to targeted therapies. While targeting mutEGFR with small-molecule tyrosine kinase inhibitors (EGFR-TKIs) dramatically improved progression-free survival in patients with non-small cell lung cancers (NSCLCs), intrinsic or acquired resistance to TKI therapy limits the duration of an effective response to TKIs. Alteration in DNA damage response (DDR) plays a vital role in genomic stability and cancer progression and helps cells to escape apoptosis, limiting the efficacy of targeted therapies.
Interestingly, lung cancer cells exposed to EGFR-TKIs demonstrate attenuated glycolytic flux - one of the major providers of precursors for de novo nucleotide synthesis. A key regulator of glycolysis is the enzyme 6-phosphofructo-2-kinase (PFKFB3). PFKFB3 synthesizes fructose 2,6-bisphosphate (F2,6BP), which is a potent allosteric activator of the glycolytic rate-limiting enzyme, 6-phosphofructo-1-kinase (PFK1). Accordingly, F2,6BP controls flux throughout the entire glycolytic pathway.
In preliminary studies, we provide evidence that PFKFB3 plays multiple roles in regulating the efficacy of DDR in lung cancer cells exposed to EGFR-TKIs. We show that PFKFB3 is required for EGFR-driven glucose metabolism, which provides a list of intermediates utilized in nucleotide synthesis. PFKFB3 regulates the expression of ribonucleotide reductase small subunit M2 (RRM2) of the ribonucleotide reductase (RNR), which is important for de novo onsite synthesis of deoxynucleotide triphosphate (dNTP) during DNA replication and repair. Moreover, a PFKFB3 inhibitor, PFK-158, increases oxidative stress in mutEGFR lung cancer cell lines and, as a result, promotes DNA damage. Importantly, we found that PFKFB3 plays an important role in the chromatin binding of scaffold proteins regulating the assembly of DNA repair complex.
Our studies suggest that PFKFB3 plays an important role in DDR and provide a clear rationale to propose the use of PFKFB3 inhibitors in combination with EGFR inhibitors to increase the efficiency and/or overcome resistance to EGFR-TKIs.
Citation Format: Nadiia Lypova, Lilibeth Lanceta, Susan Dougherty, Jason Chesney, Yoannis Imbert-Fernandez. 6-Phosphofructo-2-kinase in regulating DNA damage and repair in EGFR-driven lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6202.