Concurrent Inhibition of the RAS-MAPK Pathway and PIKfyve Is a Therapeutic Strategy for Pancreatic Cancer

Area of Science:

• Oncology
• Cell Biology
• Molecular Therapeutics

Background:

• Pancreatic ductal adenocarcinoma (PDAC) relies on KRAS signaling and autophagy for growth.
• Current treatments combining MEK inhibitors with chloroquine (CQ) show synergy but CQ has limitations.
• Developing more specific and potent autophagy inhibitors is crucial for PDAC therapy.

Purpose of the Study:

• To identify novel anti-autophagy targets in PDAC.
• To evaluate the efficacy of inhibiting phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) as an anti-autophagy strategy.
• To assess the synergistic potential of combined PIKfyve and RAS-MAPK pathway inhibition in PDAC.

Main Methods:

• Conducted a CRISPR-Cas9 loss-of-function screen in PDAC cell lines.
• Utilized the PIKfyve inhibitor apilimod and compared its effects to chloroquine.
• Investigated the impact of PIKfyve inhibition on lysosomal function, autophagic flux, and cell cycle progression.
• Assessed the combination therapy of PIKfyve and RAS-MAPK inhibitors in KRAS-mutant PDAC models.

Main Results:

• PIKfyve was identified as a key gene promoting PDAC growth.
• Apilimod demonstrated superior potency to CQ in inhibiting PDAC cell growth and causing lysosomal dysfunction.
• PIKfyve inhibition effectively blocked compensatory autophagic flux increases induced by MEK or RAS inhibition.
• Combined inhibition of PIKfyve and RAS-MAPK pathway synergistically suppressed PDAC growth, inducing cell-cycle arrest and apoptosis.

Conclusions:

• PIKfyve is a critical regulator of autophagy in KRAS-mutant PDAC.
• PIKfyve inhibition represents a potent anti-autophagy strategy with greater efficacy than CQ.
• Concurrent inhibition of PIKfyve and the RAS-MAPK pathway provides a synergistic and cytotoxic therapeutic approach for PDAC.