Dataset Information

Focus on Alectinib and Competitor Compounds for Second-Line Therapy in ALK-Rearranged NSCLC.

ABSTRACT: The management of anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) exemplifies the potential of a precision medicine approach to cancer care. The ALK inhibitor crizotinib has led to improved outcomes in the first- and second-line setting; however, toxicities, intracranial activity, and acquired resistance necessitated the advent of later generation ALK inhibitors. A large portion of acquired resistance to ALK inhibitors is caused by secondary mutations in the ALK kinase domain. Alectinib is a second-generation ALK inhibitor capable of overcoming multiple crizotinib-resistant ALK mutations and has demonstrated improved outcomes after crizotinib failure. Favorable toxicity profile and improved intracranial activity have spurred ongoing front-line trials and comparisons to other ALK inhibitors. However, important questions regarding comparability to competitor compounds, acquired alectinib resistance, and ALK inhibitor sequencing remain. Here, we review the key clinical data supporting alectinib in the second-line therapy of ALK+ NSCLC and provide context in comparison to other ALK inhibitors in development.

SUBMITTER: Tran PN

PROVIDER: S-EPMC5127851 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Focus on Alectinib and Competitor Compounds for Second-Line Therapy in <i>ALK</i>-Rearranged NSCLC.

Tran Phu N PN Klempner Samuel J SJ

Frontiers in medicine 20161130

The management of anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) exemplifies the potential of a precision medicine approach to cancer care. The ALK inhibitor crizotinib has led to improved outcomes in the first- and second-line setting; however, toxicities, intracranial activity, and acquired resistance necessitated the advent of later generation ALK inhibitors. A large portion of acquired resistance to ALK inhibitors is caused by secondary mutations in the ALK k ...[more]

PMID: 27965961

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Project description:Anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib (ALC), have dramatic therapeutic effects on ALK-rearranged lung cancer, but cures are usually not achieved. We focused on tumor cells that survive ALK inhibitor administration and hypothesized that targeted therapy for these cells could provide complete remission. To explore survival factors, we established patient-derived cell lines and screened them using proteome analysis. Three ALK-rearranged ALC-sensitive cell lines (KTOR-1, KTOR-2, KTOR-3) were established from 3 patients; the 50% inhibitory concentrations (IC50)s for ALC were 24-65 nM. Comprehensive protein expression profiles of the 3 cells indicated that exposure to ALC significantly enriched proteins related to actin and extracellular matrix (ECM) adhesion. We focused on Yes-associated protein 1 (YAP1), which is activated by ECM adhesion and actin fiber accumulation. Nuclear localization of YAP1 (an activation marker of YAP1) was assessed using immunohistostaining. In KTOR1-3 and H2228 cells from an ALK-rearranged line purchased from ATCC, exposure to ALC in vitro promoted YAP1 accumulation in the nucleus. BALB/nu mice xenograft models of H2228 or KTOR1 were administered ALC (8 mg/kg/day, N=4) or a vehicle (N=4) for 7 days, and tumors were evaluated. In ALC-administered tumors, YAP1 was localized to the nucleus, which was rarely the case in vehicle-administered tumors. The expression of pro-apoptosis factors Mcl-1 and Bcl-xL also increased after exposure to ALC in vitro, but the increment was cancelled by YAP1 inhibition by siRNA or verteporfin (VER), a non-specific YAP1 inhibitor. Exposure to ALC with combinatorial YAP1 inhibition significantly increased Caspase 3/7 activity. To address the treatment effects of YAP1 inhibition, a YAP1-activated H2228 cell line (H2ARY) was established by exposing H2228 cells to 100-300 nM of ALC for 3 months and thorough subsequent cloning. The H2ARY had lower sensitivity to ALC in vitro than parental H2228 (IC50: 1.4 μM vs 315 nM, 96 h) and restored the sensitivity by YAP1 inhibition (208 nM with VER 1 μM, 312 nM with siYAP1). Twenty-four xenograft models (mean volume: 199 mm3) of H2ARY on BALB/nu mice were randomized (Day 0) into 4 treatment groups to receive ALC monotherapy (8 mg/kg daily, N=6), VER monotherapy (12.5 mg/kg twice a week, N=7), combination (N=7), or vehicle (N=5). On day 15, the tumor volume of the vehicle and VER monotherapy groups reached > 800 mm3, with no significant differences among the groups. On day 33, the tumors of the combination group were significantly smaller than those of the ALC monotherapy group (187 vs 761 mm3, P = 0.0125). Exposure to ALC-activated YAP1 may regulate anti-apoptotic activity by controlling the expression of Mcl-1 and Bcl-xL in ALK-rearranged lung cancer cells. This is the first evidence that combinatorial therapy against ALK and YAP1 could enhance ALK-rearranged tumor treatment.

Dataset Information

Focus on Alectinib and Competitor Compounds for Second-Line Therapy in ALK-Rearranged NSCLC.

Publications

Focus on Alectinib and Competitor Compounds for Second-Line Therapy in <i>ALK</i>-Rearranged NSCLC.

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