TY - JOUR
T1 - Enhanced Vulnerability of LKB1-Deficient NSCLC to Disruption of ATP Pools and Redox Homeostasis by 8-Cl-Ado
AU - Galan-Cobo, Ana
AU - Stellrecht, Christine M.
AU - Yilmaz, Emrullah
AU - Yang, Chao
AU - Qian, Yu
AU - Qu, Xiao
AU - Akhter, Ishita
AU - Ayres, Mary L.
AU - Fan, Youhong
AU - Tong, Pan
AU - Diao, Lixia
AU - Ding, Jie
AU - Giri, Uma
AU - Gudikote, Jayanthi
AU - Nilsson, Monique
AU - Wierda, William G.
AU - Wang, Jing
AU - Skoulidis, Ferdinandos
AU - Minna, John D.
AU - Gandhi, Varsha
AU - Heymach, John V.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2022/2
Y1 - 2022/2
N2 - Loss-of-function somatic mutations of STK11, a tumor suppressor gene encoding LKB1 that contributes to the altered metabolic phenotype of cancer cells, is the second most common event in lung adenocarcinomas and often co-occurs with activating KRAS mutations. Tumor cells lacking LKB1 display an aggressive phenotype, with uncontrolled cell growth and higher energetic and redox stress due to its failure to balance ATP and NADPH levels in response to cellular stimulus. The identification of effective therapeutic regimens for patients with LKB1-deficient non–small cell lung cancer (NSCLC) remains a major clinical need. Here, we report that LKB1-deficient NSCLC tumor cells displayed reduced basal levels of ATP and to a lesser extent other nucleotides, and markedly enhanced sensitivity to 8-Cl-adenosine (8-Cl-Ado), an energy-depleting nucleoside analog. Treatment with 8-Cl-Ado depleted intracellular ATP levels, raised redox stress, and induced cell death leading to a compensatory suppression of mTOR signaling in LKB1-intact, but not LKB1-deficient, cells. Proteomic analysis revealed that the MAPK/MEK/ERK and PI3K/AKT pathways were activated in response to 8-Cl-Ado treatment and targeting these pathways enhanced the antitumor efficacy of 8-Cl-Ado.
AB - Loss-of-function somatic mutations of STK11, a tumor suppressor gene encoding LKB1 that contributes to the altered metabolic phenotype of cancer cells, is the second most common event in lung adenocarcinomas and often co-occurs with activating KRAS mutations. Tumor cells lacking LKB1 display an aggressive phenotype, with uncontrolled cell growth and higher energetic and redox stress due to its failure to balance ATP and NADPH levels in response to cellular stimulus. The identification of effective therapeutic regimens for patients with LKB1-deficient non–small cell lung cancer (NSCLC) remains a major clinical need. Here, we report that LKB1-deficient NSCLC tumor cells displayed reduced basal levels of ATP and to a lesser extent other nucleotides, and markedly enhanced sensitivity to 8-Cl-adenosine (8-Cl-Ado), an energy-depleting nucleoside analog. Treatment with 8-Cl-Ado depleted intracellular ATP levels, raised redox stress, and induced cell death leading to a compensatory suppression of mTOR signaling in LKB1-intact, but not LKB1-deficient, cells. Proteomic analysis revealed that the MAPK/MEK/ERK and PI3K/AKT pathways were activated in response to 8-Cl-Ado treatment and targeting these pathways enhanced the antitumor efficacy of 8-Cl-Ado.
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U2 - 10.1158/1541-7786.MCR-21-0448
DO - 10.1158/1541-7786.MCR-21-0448
M3 - Article
C2 - 34654720
AN - SCOPUS:85124051563
SN - 1541-7786
VL - 20
SP - 280
EP - 292
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 2
ER -