Fatty acid scavenging enables cancer escape from KRAS inhibition

Area of Science:

• Molecular oncology
• Cancer metabolism
• Drug resistance mechanisms

Background:

• Oncogenic KRAS inhibitors show efficacy but resistance is a significant clinical challenge.
• The molecular basis for KRAS inhibition resistance remains largely undefined.
• Understanding adaptive mechanisms is crucial for improving cancer therapy.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying resistance to KRAS inhibition (KRASi).
• To identify novel therapeutic targets for overcoming KRASi resistance.
• To investigate the role of metabolic reprogramming in KRASi-resistant cancers.

Main Methods:

• Analysis of KRASi-resistant cancer cell lines, particularly pancreatic cancer.
• Investigation of fatty acid (FA) metabolism, beta-oxidation, and macropinocytosis.
• Functional studies involving ADGRB1, PI3Kγ, PAK1 signaling pathways, and KRAS-PI3Kα signaling.
• Assessment of therapeutic response and patient outcomes in KRAS-mutated cancers.

Main Results:

• KRASi-resistant cells maintain mitochondrial bioenergetics via enhanced FA metabolism, independent of canonical KRAS signaling.
• Macropinocytosis is exploited to scavenge extracellular FAs, fueling beta-oxidation.
• The adhesion G protein-coupled receptor ADGRB1 drives this adaptive program through non-canonical PI3Kγ-PAK1 signaling.
• Disrupting ADGRB1-PI3Kγ signaling restores KRASi sensitivity and reverses the adaptive metabolic program.
• This pathway is prevalent in KRAS-mutated cancers and linked to poor therapeutic outcomes.

Conclusions:

• Enhanced fatty acid metabolism, driven by ADGRB1 and PI3Kγ signaling, is a key mechanism of KRASi resistance.
• Targeting the ADGRB1-PI3Kγ axis represents a promising strategy to re-sensitize cancers to KRAS inhibition.
• This metabolic adaptation is a critical vulnerability in KRAS-mutated cancers, offering new therapeutic avenues.