Abstract
Treatment resistance significantly inhibits the efficiency of targeted cancer therapies in drug-sensitive genotypes. In the current work, we studied mechanisms for rapidly occurring, adaptive resistance in targeted therapy-sensitive lung, breast, and melanoma cancer cell lines. The results show that in ALK translocated lung cancer lines H3122 and H2228, cells with cancer stem-like cell features characterized by high expression of cancer stem cell markers and/or in vivo tumorigenesis can mediate adaptive resistance to oncogene ablative therapy. When pharmacological ablation of ALK oncogene was accompanied with PI3K inhibitor or salinomycin therapy, cancer stem-like cell features were reversed which was accompanied with decreased colony formation. Furthermore, co-targeting was able to block the formation of acquired resistance in H3122 line. The results suggest that cells with cancer stem-like cell features can mediate adaptive resistance to targeted therapies. Since these cells follow the stochastic model, concurrent therapy with an oncogene ablating agent and a stem-like cell-targeting drug is needed for maximal therapeutic efficiency.
Highlights
The efficiency of targeted cancer therapies in drugsensitive genotypes such as HER2 amplified breast cancer, B-Raf mutant melanoma and ALK translocated non-small cell lung cancer (NSCLC) is significantly inhibited by treatment resistance
We hypothesized that this would be a good model for studying the mechanisms of adaptive resistance to targeted cancer therapy
Even though adaptive resistance is largely accepted as a mechanism for targeted drug resistance, it remains largely an unexplored area
Summary
The efficiency of targeted cancer therapies in drugsensitive genotypes such as HER2 amplified breast cancer, B-Raf mutant melanoma and ALK translocated non-small cell lung cancer (NSCLC) is significantly inhibited by treatment resistance. This resistance is often divided into early de novo resistance, in which cancer cells are initially unaffected by the drug, and late, acquired resistance, in which the cells gain resistance by a mechanism that abolishes the effect of the drug. Clonal evolution of cells with additional genetic alterations is another driving force for tumor heterogeneity These genetic alterations can produce cells with self-renewing and proliferating capacity resulting generation of cancer stem-like cells (CSLC) [1,2,3]
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