Relationship Between Mutant KRAS and ACLS3 Opens Door to Therapy Development for NSCLC

New research has uncovered a potential treatment target for mutant KRAS non-small cell lung cancer (NSCLC): Acyl-Coenzyme A synthetase long chain family member 3 (ACLS3).¹

ACLS3 belongs to a family of enzymes critical to fatty acid (FA) metabolism, which is essential for both β-oxidation and lipid synthesis. Its role is to commit FAs intracellularly in response to the bioenergetic demands of the cell.

Drs Padanad, Scaglioni, and colleagues found that mutant KRAS upregulates ACSL3 in lung cancer cells, both in vitro and in vivo. The suppression of ACSL3 decreases β-oxidation, leading to lower adenosine triphosphate (ATP) levels, and subsequent cell death. Like mutant KRAS expression, ACLS3 was also found to be required for tumorigenesis and for tumor maintenance.

As mutant KRAS is 1 of the most prevalent proto-oncogenes, these developments are clinically promising. In the field of cancer metabolism, the focus was previously on glucose and glutamine aberrations, as insights into the mechanism(s) of mutant KRAS’ effect remained evasive.

While approximately 30% of NSCLC tumors are affected by mutant KRAS, the mutation is implicated in up to 50% of colorectal cancers and over 90% of pancreatic cancers. Mutant KRAS tumors are also linked to a poor prognosis, particularly due to their resistance to epidermal growth factor receptor inhibitors. The development of alternative treatments is therefore imperative.

The authors of the present study are screening options for small molecule inhibitors of ACLS3. In an interview with Cancer Therapy Advisor, Dr Scaglioni, associate professor at the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas, discussed the obstacles researchers face moving forward: “The study of lipids has been difficult because the analytic platforms to analyze complex lipid mixtures in a quantitative manner are not fully developed. Many aspects of fatty acid metabolism are unknown, because mass spectrometry techniques to detect individual lipid species are not as developed as the techniques used to detect aqueous metabolites. This is an entire field that needs to be studied.”