The following is a summary of “Histone Deacetylase 6 Inhibition Exploits Selective Metabolic Vulnerabilities in LKB1 Mutant, KRAS Driven NSCLC,” published in the July 2023 issue of the Thoracic Oncology by Zhang et al.

In KRAS-mutant non-small cell lung cancer, co-occurring alterations in LKB1 impart a worse prognosis than mutations such as TP53. LKB1 is a tumor suppressor that coordinates multiple signaling pathways in response to energetic stress. Recent research on the pharmacologic and genetic inhibition of histone deacetylase 6 (HDAC6) has revealed that the activity of numerous glycolysis-related enzymes is impaired. Based on these findings, the researchers investigated the therapeutic window for HDAC6 inhibition in KRAS-mutant lung malignancies with metabolic activity. 

To control for confounding germline and somatic mutations in human models, they characterize the metabolic phenotypes at baseline and in response to HDAC6 inhibition using cell lines derived from murine autochthonous tumors harboring the KRAS/LKB1 (KL) and KRAS/TP53 mutant genotypes. The effect of HDAC6 inhibition on cancer cell growth in vitro and tumor growth in vivo was evaluated. Surprisingly, baseline levels of redox-sensitive cofactors were lower in KL-mutant cells. This is associated with an increased sensitivity to pharmacologic HDAC6 inhibition with ACY-1215 and a diminished capacity to increase compensatory metabolism and mitigate oxidative stress. 

In KL lung cancer models in vitro and in vivo, inhibiting glutaminase enhanced cell death and antitumor efficacy in pursuing synergistic metabolic combination therapies. Exploring the differential metabolism of KL and KRAS/TP53-mutant NSCLC, they discovered that KL-mutant tumors have a diminished metabolic reserve. Based on a diminished ability to compensate for impaired glycolysis, HDAC6 inhibition exploited a therapeutic window in KL NSCLC, suggesting a novel strategy for treating KRAS-mutant NSCLC with co-occurring LKB1 mutations.

Source: sciencedirect.com/science/article/pii/S1556086423001971