Metformin and salinomycin as the best combination for the eradication of NSCLC monolayer cells and their alveospheres (cancer stem cells) irrespective of EGFR, KRAS, EML4/ALK and LKB1 status.
The presence of cancer stem cells (CSCs) is linked to preexisting or acquired drug resistance and tumor relapse. Therefore, targeting both differentiated tumor cells and CSCs was suggested as an effective approach for non-small cell lung cancer (NSCLC) treatment. After screening of chemotherapeutic agents, tyrosine kinase inhibitors (TKIs) or monoclonal antibody in combination with the putative stem cell killer Salinomycin (SAL), we found Metformin (METF), which modestly exerted a growth inhibitory effect on monolayer cells and alveospheres/CSCs of 5 NSCLC cell lines regardless of their EGFR, KRAS, EML4/ALK and LKB1 status, interacted synergistically with SAL to effectively promote cell death. Inhibition of EGFR (AKT, ERK1/2) and mTOR (p70 s6k) signaling with the combination of METF and SAL can be augmented beyond that achieved using each agent individually. Phospho-kinase assay further suggested the multiple roles of this combination in reducing oncogenic effects of modules, such as ß-catenin, Src family kinases (Src, Lyn, Yes), Chk-2 and FAK. Remarkably, significant reduction of sphere formation was seen under combinatorial treatment in all investigated NSCLC cell lines. In conclusion, METF in combination with SAL could be a promising treatment option for patients with advanced NSCLC irrespective of their EGFR, KRAS, EML4/ALK and LKB1 status.
Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz, Martinsried, Germany.
Zhiguang
Z
Xiao
Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz, Martinsried, Germany.
Bianca
B
Sperl
Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz, Martinsried, Germany.
Axel
A
Ullrich
Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz, Martinsried, Germany.
Pjotr
P
Knyazev
D000091162:AMP-Activated Protein Kinase Kinases; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000008:administration & dosage; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011714:Pyrans / Q000008:administration & dosage; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D000095662:Polyether Polyketides
D000091162:AMP-Activated Protein Kinase Kinases; D018797:Cell Cycle Proteins; D066246:ErbB Receptors; D008687:Metformin; D008869:Microtubule-Associated Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D011714:Pyrans; D012697:Serine Endopeptidases; D018631:ras Proteins; C117307:KRAS protein, human; C010327:salinomycin; D000095662:Polyether Polyketides; C512478:EGFR protein, human; C109790:STK11 protein, human; C415585:EML4 protein, human