Dataset Information

Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC.

ABSTRACT: T-LAK cell-oriented protein kinase (TOPK) is a potential therapeutic target in tumors. However, its role in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) has not been reported. Here, we found that TOPK was highly expressed in ALK-positive NSCLC. Additionally, ALK was identified as another upstream kinase of TOPK by in vitro kinase assay screening. Then, it was proven that ALK phosphorylated TOPK at Y74 in vitro and ex vivo, and the pathways downstream of ALK-TOPK were explored by phosphoproteomic analysis. Subsequently, we demonstrated that inhibiting TOPK enhanced tumor sensitivity to alectinib (an ALK inhibitor). The combination of alectinib and HI-032 (a TOPK inhibitor) suppressed the growth and promoted the apoptosis of ALK-positive NSCLC cells ex vivo and in vivo. Our findings reveal a novel ALK-TOPK signaling pathway in ALK-positive NSCLC. The combination of alectinib and HI-032 might be a promising therapeutic strategy for improving the sensitivity of ALK-positive NSCLC to targeted therapy.

SUBMITTER: Xiao J

PROVIDER: S-EPMC9515217 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC.

Xiao Juanjuan J Zhang Lu L Yi Huijun H Zou Ling L Mo Jianmei J Xue Feng F Zheng Jinhua J Huang Yingze Y Lu Hui H Wu Hansheng H Xue Peipei P Zhang Xin X He Lifei L Li Zhaoxin Z Pang Shigui S Qiao Guibin G Duan Qiuhong Q Zhu Feng F

Cell death & disease 20220927 9

T-LAK cell-oriented protein kinase (TOPK) is a potential therapeutic target in tumors. However, its role in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) has not been reported. Here, we found that TOPK was highly expressed in ALK-positive NSCLC. Additionally, ALK was identified as another upstream kinase of TOPK by in vitro kinase assay screening. Then, it was proven that ALK phosphorylated TOPK at Y74 in vitro and ex vivo, and the pathways downstream of ALK-TOPK w ...[more]

PMID: 36167821

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Project description:Background: ALK inhibitors have shown positive advance in the treatment of ALK+ NSCLC. They have achieved better results in prolonging the progression free survival and improving quality of life in comparison to chemotherapy. We have assembled the evidence related to the efficacy and safety of these agents in the treatment of ALK positive NSCLC. Materials and Methods: A comprehensive search was conducted using electronic databases of PubMed, Medline and Cochrane Library to identify the studies involving comparison of ALK inhibitors to chemotherapy and Next generation ALK inhibitors to crizotinib. PFS was the primary outcome while other outcomes like ORR, adverse events, quality of life and OS were also analyzed and compared. Hazard ratios and odds ratios obtained were analyzed using fixed effect or random effects model in Review Manager Software. Results: A total of 12 studies (n = 3,297) met the criteria for inclusion in this review and meta-analysis. ALK inhibitors including crizotinib, ceritinib and alectinib revealed significantly better PFS (HR 0.42 [0.35, 0.50; p < 0.00001]), ORR (Overall OR 6.59 [4.86, 8.94; p < 0.00001] as compared to chemotherapy in the first line as well as second line treatment settings. Intracranial response rate was better with ALK inhibitors (ceritinib and alectinib) as compared to chemotherapy OR 6.51 [2.86, 14.83; p < 0.00001]. No significant increase in grade 3 or 4 adverse events was observed with crizotinib (OR 1.21 [0.82, 1.77; p = 0.34]) or ceritinib (OR 1.49 [0.86, 2.57; p = 0.17]) when compared to chemotherapy individually. Quality of life indicators assessed were significantly improved with ALK inhibitors. Next generation agents (ceritinib, alectinib and brigatinib) revealed significant improvement in PFS (HR 0.50 [0.43, 0.57; p < 0.00001]), ORR (OR 1.57 [1.21, 2.04; p = 0.0006]) in comparison to crizotinib. Next generation agents (Alectinib and brigatinib) yielded better response intra-cranially than crizotinib in terms of objective response rate (OR 5.87 [3.49, 9.87; p < 0.00001]) and time to CNS progression (HR 0.25 [0.13, 0.46; p < 0.0001]). Alectinib by far resulted in fewer adverse events than chemotherapy or crizotinib. Conclusions: Overall ALK inhibitors are safe and effective treatment option in ALK+ non-small cell lung cancer. Of the ALK inhibitors, Next generation agents in particular alectinib and brigatinib are safer and more effective intra-cranially and can be preferred as first option.

Project description:ImportanceDeregulation of anaplastic lymphoma kinase (ALK) occurs in 3-7% of advanced NSCLC mainly because of chromosomic rearrangements at the ALK locus. Next to its oncogenic function, ALK chimeric oncoprotein is a possible antigen for human immune system. The prognostic value of natural anti-ALK immunogenicity remains poorly explored in ALK + NSCLC. We hereby report preliminary results of a plasmatic anti-ALK a-abs titration assessment in a cohort of ALK + NSCLC pts.ObjectiveTo evaluate the prevalence of pre-existing circulating anti-ALK a-abs in ALK + NSCLC pts. Key secondary objectives are the assessment of anti-ALK a-abs prognostic value and association with brain metastases (BM).DesignThis monocentric case series included 60 ALK + NSCLC pts progressing on any anti-ALK TKIs between October 2015 and February 2021 at Gustave Roussy Cancer Campus. Fifty-six plasma samples were analyzed through a semiquantitative immunocytochemical technique. Plasma samples were obtained from two prospective studies approved by our Institutional Review Board: the MATCH-R trial (NCT02517892) and the MSN trial (RECF1256).ParticipantsWe included pts diagnosed with unresectable stage III or IV NSCLC, either by contemporaneous or historical biopsy. ALK-rearrangement was identified by FISH, IHC or NGS. Pts were aged more than 18-year-old and had previously signed informed consent for one of the studies. Pts had received at least one anti-ALK-TKI during the disease history. Pts were not eligible if they had been diagnosed with a second cancer.Main outcomes and measuresThe prevalence of plasmatic anti-ALK a-abs titer was reported as percentage. Progression-free survival, overall survival, and time to BM were analyzed using Kaplan-Meier methods.ResultsWe found an anti-ALK a-abs titer in 5 (9 %) pts. anti-ALK a-abs did not contribute to prolongation of survival. Although not significant, there was a trend towards protection against BM in the presence of anti-ALK a-abs.Conclusions and relevanceBecause ALK fusion proteins are exclusively produced intracellularly, not all ALK autoantibodies may have direct anti-tumor impact with favorable prognostic value. This is the first investigation to explore the impact of circulating anti-ALK a-abs on BM. Prospective studies with longer follow-up are warranted to further explore the impact of anti-ALK a-abs on BM.

Dataset Information

Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC.

Publications

Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC.

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