Enhanced Vulnerability of LKB1-Deficient NSCLC to Disruption of ATP Pools and Redox Homeostasis by 8-Cl-Ado

Ana Galan-Cobo, Christine M. Stellrecht, Emrullah Yilmaz, Chao Yang, Yu Qian, Xiao Qu, Ishita Akhter, Mary L. Ayres, Youhong Fan, Pan Tong, Lixia Diao, Jie Ding, Uma Giri, Jayanthi Gudikote, Monique Nilsson, William G. Wierda, Jing Wang, Ferdinandos Skoulidis, John D. Minna, Varsha GandhiJohn V. Heymach

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)280-292
Number of pages13
JournalMolecular Cancer Research
Volume20
Issue number2
DOIs
StatePublished - Feb 2022

ASJC Scopus subject areas

  • General Medicine

Fingerprint

Dive into the research topics of 'Enhanced Vulnerability of LKB1-Deficient NSCLC to Disruption of ATP Pools and Redox Homeostasis by 8-Cl-Ado'. Together they form a unique fingerprint.

Cite this