Abstract
Tyrosine kinase inhibitors directed against epidermal growth factor receptor (EGFR-TKI), such as erlotinib, are effective in a limited fraction of non-small cell lung cancer (NSCLC). However, the majority of NSCLC and other cancer types remain resistant. Therapeutic miRNA mimics modeled after endogenous tumor suppressor miRNAs inhibit tumor growth by repressing multiple oncogenes at once and, therefore, may be used to augment drug sensitivity. Here, we investigated the relationship of miR-34a and erlotinib and determined the therapeutic activity of the combination in NSCLC cells with primary and acquired erlotinib resistance. The drug combination was also tested in a panel of hepatocellular carcinoma cells (HCC), a cancer type known to be refractory to erlotinib. Using multiple analytical approaches, drug-induced inhibition of cancer cell proliferation was determined to reveal additive, antagonistic or synergistic effects. Our data show a strong synergistic interaction between erlotinib and miR-34a mimics in all cancer cells tested. Synergy was observed across a range of different dose levels and drug ratios, reducing IC50 dose requirements for erlotinib and miR-34a by up to 46-fold and 13-fold, respectively. Maximal synergy was detected at dosages that provide a high level of cancer cell inhibition beyond the one that is induced by the single agents alone and, thus, is of clinical relevance. The data suggest that a majority of NSCLC and other cancers previously not suited for erlotinib may prove sensitive to the drug when used in combination with a miR-34a-based therapy.
Highlights
Lung cancer accounts for the most cancer-related deaths in both men and women [1]
Lung Cancer Cells To study drug resistance in cells with acquired resistance, we used HCC827 cells that express an activating epidermal growth factor receptor (EGFR) mutation
Erlotinib-resistant cell lines were developed by exposing the parental HCC827 cells to increasing erlotinib concentrations over the course of 10 weeks until the culture showed no signs of growth inhibition at a concentration that is equivalent to IC90 in the parental cell line (Fig. 1B)
Summary
Targeted therapies are used depending on the cancer genotype or stage of disease and includes erlotinib, a small molecule inhibitor directed against epidermal growth factor receptor (EGFR). Erlotinib functions as competitive inhibitor of ATP-binding at the active site of the EGFR kinase [2]. A majority of non-small cell lung cancer (NSCLC) patients remained resistant. Primary and secondary resistance has been associated with activating KRAS mutations that may co-exist with EGFR mutations despite the fact that KRAS and EGFR mutations appeared to be predominantly mutually exclusive [5,6], an acquisition of a second mutation in the catalytic domain of EGFR (usually T790M) [7], an amplification and overexpression of receptor kinase MET and its ligand HGF, providing signals into the PI3K pathway and substituting for an inactivation of EGFR [8], increased expression of the receptor kinase AXL and its ligand GAS6 [9,10], and several others [11,12,13,14,15]
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