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Enhanced Vulnerability of LKB1-Deficient NSCLC to Disruption of ATP Pools and Redox Homeostasis by 8-Cl-Ado
Ana Galan-Cobo1, Christine M Stellrecht1,2,3, Emrullah Yilmaz1,4
1Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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. IMPLICATIONS: Together, our findings demonstrate that LKB1-deficient tumor cells are selectively sensitive to 8-Cl-Ado and suggest that therapeutic approaches targeting vulnerable energy stores combined with signaling pathway inhibitors merit further investigation for this patient population.
Insights
Loss-of-function mutations in STK11 (LKB1) are common in lung cancer. LKB1-deficient tumors are sensitive to 8-Cl-adenosine, an energy-depleting drug, offering a potential new therapy for non-small cell lung cancer.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Loss-of-function somatic mutations in STK11, encoding LKB1, are frequent in lung adenocarcinomas, often co-occurring with KRAS mutations.
- LKB1 deficiency leads to an aggressive tumor phenotype characterized by uncontrolled growth and metabolic dysregulation, including imbalanced ATP and NADPH levels.
- There is a significant clinical need for effective therapies targeting LKB1-deficient non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To investigate the therapeutic potential of targeting metabolic vulnerabilities in LKB1-deficient NSCLC.
- To evaluate the sensitivity of LKB1-deficient NSCLC cells to the nucleoside analog 8-Cl-adenosine (8-Cl-Ado).
- To explore combination strategies involving 8-Cl-Ado and signaling pathway inhibitors.
Main Methods:
- Assessment of nucleotide levels and drug sensitivity in LKB1-deficient and LKB1-intact NSCLC cells.
- Treatment with 8-Cl-Ado to analyze its effects on cellular ATP, redox stress, and cell death.
- Proteomic analysis to identify activated signaling pathways (MAPK/MEK/ERK, PI3K/AKT) post-treatment.
- Evaluation of combination therapy efficacy.
Main Results:
- LKB1-deficient NSCLC cells exhibited reduced basal ATP levels and enhanced sensitivity to 8-Cl-Ado.
- 8-Cl-Ado treatment depleted ATP, increased redox stress, and induced cell death.
- While mTOR signaling was suppressed in LKB1-intact cells, it was not in LKB1-deficient cells.
- Targeting MAPK/MEK/ERK and PI3K/AKT pathways potentiated the antitumor effects of 8-Cl-Ado.
Conclusions:
- LKB1-deficient tumor cells demonstrate selective sensitivity to 8-Cl-Ado.
- Combining energy-depleting therapies with signaling pathway inhibitors shows promise for treating LKB1-deficient NSCLC.
- Further investigation into these combined therapeutic approaches is warranted for this patient population.
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