Abstract
Non-small cell lung cancers (NSCLCs) that harbor an oncogenic KRAS mutation are often associated with resistance to targeted therapies. The MUC1-C transmembrane protein is aberrantly overexpressed in NSCLCs and confers a poor outcome; however, the functional role for MUC1-C in mutant KRAS NSCLC cells has remained unclear. The present studies demonstrate that silencing MUC1-C in A549/KRAS(G12S) and H460/KRAS(Q61H) NSCLC cells is associated with downregulation of AKT signaling and inhibition of growth. Overexpression of a MUC1-C(CQC→AQA) mutant, which inhibits MUC1-C homodimerization and function, suppressed both AKT and MEK activation. Moreover, treatment with GO-203, an inhibitor of MUC1-C homodimerization, blocked AKT and MEK signaling and decreased cell survival. The results further demonstrate that targeting MUC1-C suppresses expression of the ZEB1 transcriptional repressor by an AKT-mediated mechanism, and in turn induces miR-200c. In concert with these effects on the ZEB1/miR-200c regulatory loop, targeting MUC1-C was associated with reversal of the epithelial-mesenchymal transition (EMT) and inhibition of self-renewal capacity. Loss of MUC1-C function also attenuated KRAS independence and inhibited growth of KRAS mutant NSCLC cells as tumors in mice. These findings support a model in which targeting MUC1-C inhibits mutant KRAS signaling in NSCLC cells and thereby reverses the EMT phenotype and decreases self-renewal.
Highlights
25% of patients with non-small cell lung cancer (NSCLC) harbor an oncogenic KRAS mutation that is often associated with resistance to conventional and targeted therapies [1]
To assess the potential involvement of Mucin 1 (MUC1)-C in activated KRAS signaling, A549 cells were infected with lentiviruses expressing a control control shRNA (CshRNA) or one targeting MUC1 C-terminal subunit (MUC1-C) (MUC1shRNA) (Fig. 1A)
In A549/MUC1shRNA cells, we found that silencing MUC1-C results in decreased phosphorylation of AKT and the downstream effector S6K (Fig. 1B, left), but has no apparent effect on MEK and ERK activation (Fig. 1B, right)
Summary
25% of patients with non-small cell lung cancer (NSCLC) harbor an oncogenic KRAS mutation that is often associated with resistance to conventional and targeted therapies [1]. Pharmacologic inhibition of mutant KRAS has not as yet proven successful, a situation that has necessitated a focus on therapeutic approaches using inhibitors of the downstream AKT and MEK pathways In this context, concurrent inhibition of AKT and MEK signaling has been shown to be effective in inducing regressions of mutant Kras-driven murine lung adenocarcinomas [2] and this strategy is being evaluated for the treatment of patients with mutant KRAS NSCLC. In a small molecule screen, mutant KRAS NSCLC cells were more sensitive to inhibition of the RAF→MEK→ERK pathway as compared to KRAS wild-type cells [6]. These findings and the demonstration that sensitivity of NSCLC cells to EGFR inhibitors is inhibited by EMT [8] have supported an association between EMT and loss of oncogene addiction
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