TY - JOUR
T1 - Histone Deacetylase 6 Inhibition Exploits Selective Metabolic Vulnerabilities in LKB1 Mutant, KRAS Driven NSCLC
AU - Zhang, Hua
AU - Nabel, Christopher S.
AU - Li, Dezhi
AU - O'Connor, Ruth
AU - Crosby, Caroline R.
AU - Chang, Sarah M.
AU - Hao, Yuan
AU - Stanley, Robyn
AU - Sahu, Soumyadip
AU - Levin, Daniel S.
AU - Chen, Ting
AU - Tang, Sittinon
AU - Huang, Hsin Yi
AU - Meynardie, Mary
AU - Stephens, Janaye
AU - Sherman, Fiona
AU - Chafitz, Alison
AU - Costelloe, Naoise
AU - Rodrigues, Daniel A.
AU - Fogarty, Hilda
AU - Kiernan, Miranda G.
AU - Cronin, Fiona
AU - Papadopoulos, Eleni
AU - Ploszaj, Magdalena
AU - Weerasekara, Vajira
AU - Deng, Jiehui
AU - Kiely, Patrick
AU - Bardeesy, Nabeel
AU - Vander Heiden, Matthew G.
AU - Chonghaile, Triona Ni
AU - Dowling, Catríona M.
AU - Wong, Kwok Kin
N1 - Publisher Copyright:
© 2023 International Association for the Study of Lung Cancer
PY - 2023/7
Y1 - 2023/7
N2 - Introduction: 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. Methods: 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. Results: 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. Conclusions: 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.
AB - Introduction: 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. Methods: 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. Results: 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. Conclusions: 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.
KW - Glutaminase inhibition
KW - Glycolysis
KW - HDAC6
KW - KRAS
KW - LKB1
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=85152096714&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2023.03.014
DO - 10.1016/j.jtho.2023.03.014
M3 - Article
C2 - 36958689
AN - SCOPUS:85152096714
SN - 1556-0864
VL - 18
SP - 882
EP - 895
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 7
ER -