Simultaneous suppression of PKM2 and PHGDH elicits synergistic anti-cancer effect in NSCLC

Area of Science:

• Oncology
• Cancer Metabolism

Background:

• Metabolic reprogramming, particularly enhanced glycolysis, is a key feature of cancer.
• Glycolytic intermediates can be rerouted to support cancer cell biosynthesis.
• Pyruvate kinase M2 (PKM2) and phosphoglycerate dehydrogenase (PHGDH) are key enzymes in cancer metabolism.

Purpose of the Study:

• To investigate the anti-cancer effects of PKM2 inhibitor PKM2-IN-1 and PHGDH inhibitor NCT-503 in non-small cell lung cancer (NSCLC).
• To evaluate the efficacy of the combination therapy in vitro and in vivo.

Main Methods:

• Utilized human NSCLC A549 cells for in vitro studies.
• Administered PKM2-IN-1 and NCT-503 alone and in combination.
• Assessed effects on cell proliferation, cell cycle, apoptosis, ATP levels, AMPK/mTOR signaling, and protein expression.
• Conducted in vivo studies using A549 tumor xenografts.

Main Results:

• PKM2-IN-1 inhibited proliferation, induced cell cycle arrest and apoptosis, increasing 3-phosphoglycerate (3-PG) and PHGDH.
• The combination therapy further suppressed proliferation, induced G2/M arrest, reduced ATP, activated AMPK, and modulated key cell cycle and apoptosis proteins.
• Combined treatment induced ROS-dependent apoptosis and suppressed glucose transporter type 1 (GLUT1) expression.
• In vivo, the combination significantly inhibited tumor growth.

Conclusions:

• The combination of PKM2-IN-1 and NCT-503 demonstrates significant anti-cancer effects in NSCLC.
• Therapeutic mechanisms involve G2/M cell cycle arrest, apoptosis induction, metabolic stress, and ROS generation.
• This combination represents a potential therapeutic strategy for lung cancer treatment.