Targeting BMI1 and MCL1 for Lung Adenocarcinoma Treatment

Lung cancer is the leading cause of cancer-associated death worldwide. Early metastasis and the recurrence remain major challenges for lung cancer treatment in clinic. Targeting the cancer stemness could be a potential strategy to restrain tumor progression. In the current study, we found that in lung adenocarcinoma (LAC), BMI1 and MCL1 play crucial roles in invasion, chemo-resistance, and tumor initiation. JNK signaling is a link between oncogenic pathway or environment stress to cancer stemness. The activation of JNK, either by EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3-ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small-molecule BI-44 was synthesized, which effectively suppressed BMI1/MCL1 expression and inhibited tumor formation and progression in preclinical models. Targeting BMI1/MCL1 provides the basis for a new therapeutic approach in the treatment of LAC.

[1]  F. de Marinis,et al.  Concise Review: Resistance to Tyrosine Kinase Inhibitors in Non‐Small Cell Lung Cancer: The Role of Cancer Stem Cells , 2018, Stem cells.

[2]  Natalya A Ortolano,et al.  A Non-apoptotic Function of MCL-1 in Promoting Pluripotency and Modulating Mitochondrial Dynamics in Stem Cells , 2018, Stem cell reports.

[3]  W. Curran,et al.  Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy , 2017, The Journal of clinical investigation.

[4]  H. Clevers,et al.  Cancer stem cells revisited , 2017, Nature Medicine.

[5]  Changting Liu,et al.  Bmi-1 overexpression as an efficient prognostic marker in patients with nonsmall cell lung cancer , 2017, Medicine.

[6]  Tatsuya Shimizu,et al.  Dinaciclib potently suppresses MCL-1 and selectively induces the cell death in human iPS cells without affecting the viability of cardiac tissue , 2017, Scientific Reports.

[7]  A. Iwama,et al.  The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells , 2017, Blood Cancer Journal.

[8]  M. Tiseo,et al.  Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance. , 2016, Translational lung cancer research.

[9]  T. Pandita,et al.  MCL-1 Depletion Impairs DNA Double-Strand Break Repair and Reinitiation of Stalled DNA Replication Forks , 2016, Molecular and Cellular Biology.

[10]  Y. Fernández-Marrero,et al.  Survival control of malignant lymphocytes by anti-apoptotic MCL-1 , 2016, Leukemia.

[11]  Kol Jia Yong,et al.  Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPα expression , 2016, Science Translational Medicine.

[12]  M. Kuo,et al.  C‐Jun N‐terminal kinase signalling pathway in response to cisplatin , 2016, Journal of cellular and molecular medicine.

[13]  A. Sahasrabuddhe.  BMI1: A Biomarker of Hematologic Malignancies , 2016, Biomarkers in cancer.

[14]  L. Howell,et al.  Small‐Molecule and Peptide Inhibitors of the Pro‐Survival Protein Mcl‐1 , 2015, ChemMedChem.

[15]  F. Wei,et al.  A Novel Aspect of Tumorigenesis—BMI1 Functions in Regulating DNA Damage Response , 2015, Biomolecules.

[16]  M. Andreeff,et al.  Preclinical activity of the novel B‐cell‐specific Moloney murine leukemia virus integration site 1 inhibitor PTC‐209 in acute myeloid leukemia: Implications for leukemia therapy , 2015, Cancer science.

[17]  A. Strasser,et al.  Antagonism between MCL-1 and PUMA governs stem/progenitor cell survival during hematopoietic recovery from stress. , 2015, Blood.

[18]  Robert L. Judson,et al.  CDK1 Inhibition Targets the p53-NOXA-MCL1 Axis, Selectively Kills Embryonic Stem Cells, and Prevents Teratoma Formation , 2015, Stem cell reports.

[19]  Jingting Jiang,et al.  Prognostic role of high Bmi-1 expression in Asian and Caucasian patients with solid tumors: a meta-analysis. , 2014, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[20]  T. Davis,et al.  Abstract 5517: PTC596-induced Bmi1 hyper-phosphorylation via Cdk1/2 activation resulting in tumor stem cell depletion , 2014 .

[21]  Dana M. Brantley-Sieders,et al.  JNK signaling mediates EPHA2-dependent tumor cell proliferation, motility, and cancer stem cell-like properties in non-small cell lung cancer. , 2014, Cancer research.

[22]  D. Pisani,et al.  The Role of BMI1 as a Biomarker of Cancer Stem Cells in Head and Neck Cancer: A Review , 2014, Oncology.

[23]  S. Papa,et al.  JNK signalling in cancer: in need of new, smarter therapeutic targets , 2014, British journal of pharmacology.

[24]  A. Krešo,et al.  Self-renewal as a therapeutic target in human colorectal cancer , 2013, Nature Medicine.

[25]  C. Tournier.  The 2 Faces of JNK Signaling in Cancer. , 2013, Genes & cancer.

[26]  G. Pagès,et al.  Linking JNK Activity to the DNA Damage Response. , 2013, Genes & cancer.

[27]  A. Roulston,et al.  Programming cancer cells for high expression levels of Mcl1 , 2013, EMBO reports.

[28]  M. Saleem,et al.  CANCER STEM CELLS Concise Review: Role of BMI1, a Stem Cell Factor, in Cancer Recurrence and Chemoresistance: Preclinical and Clinical Evidences , 2012 .

[29]  Fei Chen.  JNK-induced apoptosis, compensatory growth, and cancer stem cells. , 2012, Cancer research.

[30]  O. Klein,et al.  A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable , 2011, Nature.

[31]  T. Davis,et al.  BMI1 as a novel target for drug discovery in cancer , 2011, Journal of cellular biochemistry.

[32]  Zachary D. Smith,et al.  Lung stem cell self-renewal relies on BMI1-dependent control of expression at imprinted loci. , 2011, Cell stem cell.

[33]  Goberdhan P Dimri,et al.  βTrCP regulates BMI1 protein turnover via ubiquitination and degradation , 2011, Cell cycle.

[34]  A. Godwin,et al.  The role of the c-Jun N-terminal kinase 2-α-isoform in non-small cell lung carcinoma tumorigenesis , 2011, Oncogene.

[35]  C. Scott,et al.  Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance. , 2010, Blood.

[36]  B. Leber,et al.  The human stem cell hierarchy is defined by a functional dependence on Mcl-1 for self-renewal capacity. , 2010, Blood.

[37]  V. Duronio,et al.  MCL-1 localizes to sites of DNA damage and regulates DNA damage response , 2010, Cell cycle.

[38]  I. Leray,et al.  ATM-dependent expression of IEX-1 controls nuclear accumulation of Mcl-1 and the DNA damage response , 2010, Cell Death and Differentiation.

[39]  Derek Y. Chiang,et al.  The landscape of somatic copy-number alteration across human cancers , 2010, Nature.

[40]  J. Lees,et al.  Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion , 2008, Proceedings of the National Academy of Sciences.

[41]  V. Duronio,et al.  An essential role for MCL-1 in ATR-mediated CHK1 phosphorylation. , 2008, Molecular biology of the cell.

[42]  J. Pollack,et al.  c-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells , 2007, Oncogene.

[43]  Xiaodong Wang,et al.  Mule/ARF-BP1, a BH3-Only E3 Ubiquitin Ligase, Catalyzes the Polyubiquitination of Mcl-1 and Regulates Apoptosis , 2005, Cell.

[44]  S. Korsmeyer,et al.  Obligate Role of Anti-Apoptotic MCL-1 in the Survival of Hematopoietic Stem Cells , 2005, Science.

[45]  R. Davis,et al.  Signal Transduction by the JNK Group of MAP Kinases , 2000, Cell.

[46]  S. Fesik,et al.  Small molecule Mcl-1 inhibitors for the treatment of cancer. , 2015, Pharmacology & therapeutics.