Tankyrase 2 as a therapeutic target in non-small cell lung cancer: Implications for apoptosis and migration

Abstract

This letter addresses Wang and Zhang's investigation into the role of tankyrase 2 (TNKS2) as a pivotal driver of malignancy in non-small cell lung cancer (NSCLC) through mechanisms including apoptosis inhibition, enhanced cellular migration, and β-catenin pathway activation. Their study in NSCLC cell lines demonstrates that TNKS2 overexpression stabilizes β-catenin, subsequently triggering oncogenic gene expression and facilitating cellular migration-key attributes of metastatic potential. These insights position TNKS2 as a compelling target for therapy and a potential prognostic marker in NSCLC. Nevertheless, translating these in vitro findings to clinical practice requires validation in in vivo models. Additionally, further research should investigate TNKS2 expression in patient samples and assess its implications in therapy resistance and combination treatment strategies.

Key Words: Apoptosis; Cell migration; Metastasis; Non-small cell lung cancer; Therapeutic target

Core Tip: Tankyrase 2 (TNKS2) drives the progression of non-small cell lung cancer (NSCLC) by inhibiting apoptosis and promoting cell migration, significantly activating the β-catenin pathway. This function underscores TNKS2's potential as a therapeutic target in NSCLC; however, additional in vivo studies are needed to confirm its role and to evaluate its expression in clinical samples for prognostic use. Combining TNKS2 inhibitors with apoptosis-inducing drugs may enhance therapeutic efficacy, while targeted delivery methods could reduce off-target effects in healthy tissues, advancing the development of TNKS2-focused treatment strategies in NSCLC management.

TO THE EDITOR

I was very intrigued by the recent publication by Wang and Zhang[1], titled “Tankyrase 2 Promotes Lung Cancer Cell Malignancy”, in the World Journal of Clinical Oncology. This study explores the critical and multifaceted role of tankyrase 2 (TNKS2) in non-small cell lung cancer (NSCLC), with a particular focus on TNKS2’s impact on apoptosis inhibition, enhanced cell migration, and its interaction with the β-catenin signaling pathway. The findings present compelling evidence that TNKS2 serves not only as a driver of tumor progression but also as a potential prognostic marker and therapeutic target in NSCLC.

Key findings and mechanisms

The authors[1] demonstrated that stable overexpression and knockdown of TNKS2 in A549 and H647 lung cancer cell lines significantly influence cell survival and migration, thereby contributing to NSCLC malignancy. Their approach-utilizing lentiviral-mediated gene modulation coupled with detailed assessments of apoptosis, migration, and protein expression-provides a robust foundation for examining TNKS2’s molecular functions in NSCLC. The study’s finding that TNKS2 overexpression enhances β-catenin nuclear localization and activation highlights a crucial mechanism through which TNKS2 may drive oncogenesis via the Wnt/β-catenin pathway.

A key finding is the pronounced anti-apoptotic effect of TNKS2, which aligns with prior studies linking β-catenin activation to tumor cell survival[2]. This study bolsters the hypothesis that TNKS2 stabilizes β-catenin by disrupting its degradation complex with axin, resulting in nuclear accumulation of β-catenin and subsequent activation of oncogenic target genes. This insight into the TNKS2/β-catenin axis has significant therapeutic implications for NSCLC, as the Wnt/β-catenin pathway is increasingly recognized as critical to cancer progression. However, the study’s reliance on in vitro models raises questions about the applicability of these findings to clinical settings. Future research should prioritize in vivo models to confirm TNKS2’s role in tumorigenesis and evaluate the impact of TNKS2 inhibition within the intricate tumor microenvironment.

Additionally, TNKS2’s influence on cellular migration was effectively demonstrated in this study using scratch assays, which showed that TNKS2 overexpression enhances NSCLC cell migration. Migration and invasion are critical markers of metastatic potential, suggesting that TNKS2 contributes not only to local tumor growth but also to the dissemination of cancer cells to distant sites. Given that NSCLC commonly metastasizes to the brain, bones, and liver, understanding the mechanisms driving this process is essential. The observed effect of TNKS2 on migration underscores the need for further investigation into its role in metastasis in vivo. Studies with animal models of lung cancer metastasis could provide insights into whether TNKS2 inhibitors might effectively restrict NSCLC cell spread, offering potential improvements in patient outcomes.

Clinical implications and future directions

Assessing TNKS2 expression levels in NSCLC patient samples is also essential. While this study offers preliminary insights into TNKS2’s role in cultured cell lines, examining its expression across various stages and subtypes of NSCLC-ideally through high-throughput analyses of patient biopsies or databases-could yield valuable data[3]. Such studies could clarify whether TNKS2 expression correlates with tumor grade, stage, or patient prognosis, further supporting its potential as a clinical biomarker. Additionally, investigating TNKS2 expression in treatment-resistant NSCLC subtypes, such as EGFR or KRAS-mutant tumors, could reveal insights into its role in therapy resistance-a significant challenge in NSCLC treatment[4].

This study highlights the potential of TNKS2 as a therapeutic target, though significant challenges remain. TNKS2's role within the Wnt/β-catenin pathway is complex and context-dependent; while TNKS2-mediated β-catenin stabilization benefits cancer cell survival, this pathway is tightly regulated in normal cells and essential for tissue homeostasis[5]. Consequently, systemic TNKS2 inhibition must be approached with caution, as it may disrupt Wnt signaling in healthy tissues, leading to potential adverse effects[6,7]. Future studies should, therefore, explore targeted delivery strategies to localize TNKS2 inhibitors specifically to cancer cells. Approaches such as nanoparticle-based drug delivery or antibody-drug conjugates could help minimize off-target effects[8].

Moreover, the authors[1]' findings on TNKS2’s role in apoptosis suppression suggest promising opportunities for combination therapy. Inhibiting TNKS2 could potentially sensitize NSCLC cells to apoptosis-inducing chemotherapeutics, thereby enhancing treatment efficacy[9]. Given the high recurrence rates and poor prognosis associated with advanced NSCLC, combining TNKS2 inhibitors with standard chemotherapies or novel immunotherapies may yield better outcomes. Studies investigating the synergistic effects of TNKS2 inhibitors with apoptosis-inducing agents, such as cisplatin or immune checkpoint inhibitors, could provide valuable insights into the potential of these combination strategies[10].

Conclusion

In conclusion, Wang and Zhang[1] present a compelling case for TNKS2 as a significant contributor to NSCLC malignancy and a promising therapeutic target. By clarifying TNKS2’s role in apoptosis inhibition, migration promotion, and β-catenin pathway activation, this study makes a meaningful contribution to the ongoing investigation of molecular drivers in NSCLC. Future research should extend these findings to in vivo models and assess TNKS2’s clinical relevance in patient samples. With continued study, TNKS2-targeted therapies could become a valuable addition to the NSCLC treatment landscape, offering hope for more effective management of this aggressive cancer.