Abstract
Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer.
Highlights
Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure
The present results showed the activation of Yes-associated protein 1 (YAP1) by ALC using an evaluation of ALK-rearranged cancer cells that survived a treatment with ALC
We have demonstrated that YAP1 mediates initial survival from or resistance to ALK inhibitors via anti-apoptotic factors (Fig. 8b)
Summary
Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Using patient-derived cell line models, we demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALKrearranged xenografts when compared with alectinib monotherapy These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer. Even with ALK inhibition using highly specific ALK inhibitors, a small subpart of tumors generally survives the initial phase of treatment This ‘initial survival’ of cancer cells from targeted therapy against driver oncogenes has recently been highlighted in epidermal growth factor receptor (EGFR)-mutated tumors, and the Notch-3/β-catenin pathway or AXL has been shown to play a key role in this survival[18,19,20]. We consider combinatorial therapy against ALK and YAP1 to be a promising therapy that enhances treatment effects in ALKrearranged lung cancer
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