Rho GTPase effectors and NAD metabolism in cancer immune suppression

ABSTRACT

Introduction: Sustained proliferative signaling and de-regulated cellular bioenergetics are two of the chief hallmarks of cancer. Alterations in the Ras pathway and its downstream effectors are among the major drivers for uncontrolled cell growth in many cancers. The GTPases are one of the signaling molecules that activate crucial signal transducing pathways downstream of Ras through several effector proteins. The GTPases (GTP bound) interact with several effectors and modulate a number of different biological pathways including those that regulate cytoskeleton, cellular motility, cytokinesis, proliferation, apoptosis, transcription and nuclear signaling. Similarly, the altered glycolytic pathway, the so-called ‘Warburg effect’, rewires tumor cell metabolism to support the biosynthetic requirements of uncontrolled proliferation. There exists strong evidence for the critical role of the glycolytic pathway’s rate limiting enzymes in promoting immunosuppression.

Areas covered: We review the emerging roles of GTPase effector proteins particularly the p21 activated kinase 4 (PAK4) and nicotinamide biosynthetic pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) as signaling molecules in immune surveillance and the immune response.

Expert opinion: In this expert opinion article we highlight the recent information on the role of GTPases and the metabolic enzymes on the immune microenvironment and propose some unique immune therapeutic opportunities.

KEYWORDS:

• P21 activated kinases
• PAK4
• NAD
• NAMPT
• NAPRT
• immune checkpoint
• PD-1
• PD-L1
• Ras
• GTPase
• PAK4 inhibitor
• NAMPT inhibitor

Article highlights

• Immune checkpoint inhibition has shown limited success clinically.

• There is emerging knowledge on the role of Rho GTPase effectors and tumor cells' glycolytic signaling pathways in tumor immune suppression.

• Dual PAK4-NAMPT inhibition could become an effective targeted therapy that affects tumor immune suppression.

• Combining PAK4-NAMPT and immune checkpoint inhibition serves as a promising anti-cancer strategy.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

Work in the lab of A. S. Azmi is supported by NIH grant 1R21CA188818-01A1. The authors also acknowledge the generous support of SKY foundation Inc. for pancreas cancer research.