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Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer.

ABSTRACT: Clinical benefit of ALK tyrosine kinase inhibitors (ALK-TKIs) in ALK-rearranged lung cancer has been limited by the inevitable development of acquired resistance, and bypass-molecular resistance mechanisms remain poorly understood. We investigated a novel therapeutic target through screening FDA-approved drugs in ALK-TKI-resistant models. Cerivastatin, the rate-limiting enzyme inhibitor of the mevalonate pathway, showed anti-cancer activity against ALK-TKI resistance in vitro/in vivo, accompanied by cytoplasmic retention and subsequent inactivation of transcriptional co-regulator YAP. The marked induction of YAP-targeted oncogenes (EGFR, AXL, CYR61, and TGF?R2) in resistant cells was abolished by cerivastatin. YAP silencing suppressed tumor growth in resistant cells, patient-derived xenografts, and EML4-ALK transgenic mice, whereas YAP overexpression decreased the responsiveness of parental cells to ALK inhibitor. In matched patient samples before/after ALK inhibitor treatment, nuclear accumulation of YAP was mainly detected in post-treatment samples. High expression of YAP in pretreatment samples was correlated with poor response to ALK-TKIs. Our findings highlight a crucial role of YAP in ALK-TKI resistance and provide a rationale for targeting YAP as a potential treatment option for ALK-rearranged patients with acquired resistance to ALK inhibitors.

SUBMITTER: Yun MR

PROVIDER: S-EPMC6895608 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer.

Yun Mi Ran MR Choi Hun Mi HM Lee You Won YW Joo Hyeong Seok HS Park Chae Won CW Choi Jae Woo JW Kim Dong Hwi DH Kang Han Na HN Pyo Kyoung-Ho KH Shin Eun Joo EJ Shim Hyo Sup HS Soo Ross A RA Yang James Chih-Hsin JC Lee Sung Sook SS Chang Hyun H Kim Min Hwan MH Hong Min Hee MH Kim Hye Ryun HR Cho Byoung Chul BC

EMBO molecular medicine 20191021 12

Clinical benefit of ALK tyrosine kinase inhibitors (ALK-TKIs) in ALK-rearranged lung cancer has been limited by the inevitable development of acquired resistance, and bypass-molecular resistance mechanisms remain poorly understood. We investigated a novel therapeutic target through screening FDA-approved drugs in ALK-TKI-resistant models. Cerivastatin, the rate-limiting enzyme inhibitor of the mevalonate pathway, showed anti-cancer activity against ALK-TKI resistance in vitro/in vivo, accompanie ...[more]

PMID: 31633304

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Project description:Background and objectiveAnaplastic lymphoma kinase (ALK) rearrangements are detected in 3-7% of advanced non-small cell lung cancer (NSCLC). There are currently 5 U.S Food and Drug Administration (FDA)-approved ALK tyrosine kinase inhibitors (TKIs) for the treatment of patients with ALK-positive lung cancer in the advanced/metastatic disease setting. Despite these advances, most patients with ALK-positive lung cancer who are treated with ALK TKI therapy ultimately experience disease progression due to various mechanisms of drug resistance. In this review, we discuss strategies to address acquired therapeutic resistance to ALK inhibition, novel agents and combinatorial strategies in development for both on and off-target resistance, and some emerging approaches to prolong response to ALK inhibitors.MethodsWe performed a search of peer-reviewed literature in the English language, conference abstracts, and trial registrations from the MEDLINE (Ovid), Embase (Elsevier), and CENTRAL (Cochrane Library) databases and major international oncology meetings up to August 2022. We then screened for studies describing interventions to overcome ALK resistance based on review of each title and abstract.Key content and findingsFor patients with oligo-progression, treatment may include maintaining the same systemic treatment beyond progression while adding local therapies to progressing lesions. Strategies to combat ALK TKI resistance mediated by on-target resistance mechanisms include 4th generation TKIs (TPX-0131, NVL-655) and proteolysis-targeting chimeras (PROTACs) currently in development. While for those patients who develop tumor progression due to off-target (ALK independent) resistance, options may include combination therapies targeting ALK and other downstream or parallel pathways, novel antibody drug conjugates, or combinations of ALK inhibitors with chemotherapy and immunotherapy. Lastly, other potential strategies being explored in the clinic include circulating tumor DNA (ctDNA) surveillance to monitor for molecular mediators of drug resistance prior to frank progression on imaging studies and utilization of ALK TKIs in the adjuvant and neoadjuvant settings.ConclusionsStrategies to overcome resistance to currently available ALK inhibitors are urgently needed. Given the variety of resistance mechanisms, tailormade approaches are required for disease control.

Dataset Information

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer.

Publications

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer.

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