Abstract
Overcoming acquired drug resistance is a primary challenge in cancer treatment. Notably, more than 50% of patients with BRAFV600E cutaneous metastatic melanoma (CMM) eventually develop resistance to BRAF inhibitors. Resistant cells undergo metabolic reprogramming that profoundly influences therapeutic response and promotes tumor progression. Uncovering metabolic vulnerabilities could help suppress CMM tumor growth and overcome drug resistance. Here we identified a drug, HA344, that concomitantly targets two distinct metabolic hubs in cancer cells. HA344 inhibited the final and rate-limiting step of glycolysis through its covalent binding to the pyruvate kinase M2 (PKM2) enzyme, and it concurrently blocked the activity of inosine monophosphate dehydrogenase, the rate-limiting enzyme of de novo guanylate synthesis. As a consequence, HA344 efficiently targeted vemurafenib-sensitive and vemurafenib-resistant CMM cells and impaired CMM xenograft tumor growth in mice. In addition, HA344 acted synergistically with BRAF inhibitors on CMM cell lines in vitro. Thus, the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers. Significance: Glycolytic and purine synthesis pathways are often deregulated in therapy-resistant tumors and can be targeted by the covalent inhibitor described in this study, suggesting its broad application for overcoming resistance in cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3806-3821 |
| Number of pages | 16 |
| Journal | Cancer Research |
| Volume | 81 |
| Issue number | 14 |
| DOIs | |
| State | Published - Jul 15 2021 |
Funding
The authors sincerely thank P. Marchetti and J. Kluza (INSERM 1185 U837, equipe 4, Lille, France) for A375 melanoma-resistant cell lines. They particularly thank R. Tomaino (Taplin Mass Spectrometry Facility, Harvard) for the mass spectrometry analysis. The authors thank all the platforms at C3M: microscopy (M. Gesson), cytometry (M. Nebout), and animal facility (V. Corcelle). This research was supported by the INSERM, University of Nice Sophia-Antipolis, Fondation pour la Recherche Médicale (EQU202003010248), the French Government (National Research Agency, ANR) through the “Investments for the Future” programs LABEX SIGNALIFE ANR-11-LABX-0028-01 and IDEX UCAJedi ANR-15-IDEX-01, Fon-dation ARC (2018–2020), ITMO Cancer (2019–2021), Canceropole PACA, and Association Laurette Fugain (ALF 2016/08). M. Zerhouni is a recipient of a doctoral fellowship from Labex SIGNALIFE. This work was also funded by the French government (National Research Agency, ANR) through the “investissement for the future” LABEX SIGNALIFE program reference #ANR-11-1200 LABEX-0028-01. M. Zerhouni is a recipient of a doctoral fellowship from the LABEX 1201 Signalife and Fondation pour la Recherche Médicale. This work has been supported by the French government through the UCAJEDI Investments in the Future project managed by the National Research Agency (ANR) with the reference number ANR-15-IDEX-01. Team 12 of corresponding author, S. Rocchi, is Equipe Labélisée de la Fondation pour la Recherche Médicale. M. Zerhouni reports grants and personal fees from Fondation pour la recherche Médicale and Labex SIGNALIFE and grants from National Research Agency (ANR), UCAJedi ANR-15-IDEX-01, Fondation ARC, and ITMO Cancer during the conduct of the study. No disclosures were reported by the other authors.
ASJC Scopus subject areas
- Oncology
- Cancer Research
