Abstract
The fusion between anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) is a causative factor in a unique subset of patients with non-small cell lung carcinoma (NSCLC). Although the inhibitor crizotinib, as it blocks the kinase activity of the resulting EML4-ALK fusion protein, displays remarkable initial responses, a fraction of NSCLC cases eventually become resistant to crizotinib by acquiring mutations in the ALK domain or activating bypass pathways via EGFR, KIT, or KRAS. Cancer stem cell (CSC) theory provides a plausible explanation for acquisition of tumorigenesis and resistance. However, the question as to whether EML4-ALK-driven tumorigenesis is linked with the stem-like property and whether the stemness is an effective target in controlling EML4-ALK+ NSCLC including crizotinib-resistant NSCLC cells has not been addressed. Here, we report that stem-like properties stem from ALK activity in EML4-ALK+ NSCLC cells. Notably, treatment with rapamycin, a CSC targeting agent, attenuates stem-like phenotypes of the EML4-ALK+ cells, which increased capability of tumor formation and higher expression of stemness-associated molecules such as ALDH, NANOG, and OCT4. Importantly, combinational treatment with rapamycin and crizotinib leads to synergistic anti-tumor effects on EML4-ALK+ NSCLC cells as well as on those resistant to crizotinib. Thus, we provide a proof of principle that targeting stemness would be a novel strategy to control intractable EML4-ALK+ NSCLC.
Highlights
About 3%–7% of non-small cell lung carcinoma (NSCLC) tumors are driven by an activating fusion of anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) genes [1, 2]
Our findings show that Cancer stem cell (CSC) drugs targeting stem-like traits of cancer cells could be effective in controlling refractory EML4-ALK+ NSCLC
To assess the molecular basis for the enhanced stem-like phenotype of EML4-ALK+ cells, we examined the expression of the stem cell related molecules such as NANOG, OCT4, SOX2, KLF4, and c-MYC and the activated form of ALK, phospho-ALK (Y1604), through western blot analysis with lysates of the monolayer-cultured cells
Summary
About 3%–7% of NSCLC tumors are driven by an activating fusion of anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) genes [1, 2]. The acquired resistance to crizotinib is highly associated with secondary mutations in the ALK tyrosine kinase domain and amplification of the ALK fusion gene. Non-gatekeeper mutations such as L1152R, C1156Y, and G1269A, were proposed to be www.impactjournals.com/oncotarget associated with resistance to inhibitors used in the treatment of ALK+ NSCLC [5,6,7]. Another mechanism of ALK-dependent resistance occurs upon activation of alternative signaling pathways via EGFR, KIT, or KRAS with known tumor promoting properties [8,9,10,11]. There is an urgent need to clinically develop a novel and fundamental strategy which can break the vicious cycle of acquired ALK resistance
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have