Abstract
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.
Highlights
Lung cancer is the leading cause of tumor-related death and accounts for the most common malignancy in the world
Mutations in Epidermal growth factor receptor (EGFR), KRAS and anaplastic lymphoma kinase (ALK) are mutually exclusive in individual tumors; KRAS oncogene activation is coincident with liver kinase B1 (LKB1) deficiency in 7-10% of all nonsmall cell lung cancer (NSCLC) [6]
These morphological characteristics of 3D outgrowth of these cell lines could indicate the existence of a functional heterogeneity of cancer stem cells (CSCs), which may vary from tumor to tumor, depending on their mutations and distinct genetic profiles
Summary
Lung cancer is the leading cause of tumor-related death and accounts for the most common malignancy in the world. Epidermal growth factor receptor (EGFR) is highly expressed on the cell surface of > 60% of nonsmall cell lung cancer (NSCLC) [1]. Intrinsic or acquired resistance limits the therapeutic success of these targeted agents. The other EGFR mutations, occur relatively rarely with < 10% of cases, of which the T790M substitution can either be linked to primary resistance to abrogate the inhibitory activity of TKIs, or might be presented as the secondary mutation bypassing the continued requirement for the original target. The mutation frequencies of KRAS, anaplastic lymphoma kinase (ALK) and liver kinase B1 (LKB1) are approximately 25%, 3-7% and 15-30% of NSCLCs, respectively [4, 5]. Mutations in EGFR, KRAS and ALK are mutually exclusive in individual tumors; KRAS oncogene activation is coincident with LKB1 deficiency in 7-10% of all NSCLC [6]
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