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Histone deacetylase 6 inhibition exploits selective metabolic vulnerabilities in LKB1 mutant, KRAS driven non-small cell lung cancer
In KRAS-mutant NSCLC, co-occurring alterations in LKB1 confer a negative prognosis compared with other mutations such as TP53. LKB1 is a tumor suppressor that coordinates several signaling pathways in response to energetic stress. Our recent work on pharmacologic and genetic inhibition of histone deacetylase 6 (HDAC6) revealed the impaired activity of numerous enzymes involved in glycolysis. On the basis of these previous findings, we explored the therapeutic window for HDAC6 inhibition in metabolically-active KRAS-mutant lung tumors.
Using cell lines derived from mouse autochthonous tumors bearing the KRAS/LKB1 (KL) and KRAS/TP53 mutant genotypes to control for confounding germline and somatic mutations in human models, we characterize the metabolic phenotypes at baseline and in response to HDAC6 inhibition. The impact of HDAC6 inhibition was measured on cancer cell growth in vitro and on tumor growth in vivo.
Surprisingly, KL-mutant cells revealed reduced levels of redox-sensitive cofactors at baseline. This is associated with increased sensitivity to pharmacologic HDAC6 inhibition with ACY-1215 and blunted ability to increase compensatory metabolism and buffer oxidative stress. Seeking synergistic metabolic combination treatments, we found enhanced cell killing and antitumor efficacy with glutaminase inhibition in KL lung cancer models in vitro and in vivo.
Exploring the differential metabolism of KL and KRAS/TP53-mutant NSCLC, we identified decreased metabolic reserve in KL-mutant tumors. HDAC6 inhibition exploited a therapeutic window in KL NSCLC on the basis of a diminished ability to compensate for impaired glycolysis, nominating a novel strategy for the treatment of KRAS-mutant NSCLC with co-occurring LKB1 mutations.
Development of a novel genetically engineered mouse model to study the role of HDAC6 in oncogenesis and metastasis of non-small cell lung cancer.
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PublicationJournal of Thoracic Oncology, 2023, 18 (7), pp. 882-895
Other Funding informationThis work was supported by the NCI grants (ROICA219670, PO1CA15430) (KKW) and the H2020 MSCA Global Fellowship (799724) (CMD)
RightsThis is the author’s version of a work that was accepted for publication in Journal of Thoracic Oncology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Thoracic Oncology 2023, 18 (7), pp. 882-895, https://doi.org/10.1016/j.jtho.2023.03.014
Also affiliated with
- Health Research Institute (HRI)
Sustainable development goals
- (3) Good Health and Well-being
Department or School
- School of Medicine