Biology and impact of lineage plasticity in ALK-positive NSCLC: a narrative review

Meador, Catherine B.; Piotrowska, Zofia

doi:10.21037/tlcr-22-867

Cited by 8 publications

(3 citation statements)

References 144 publications

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“…Therefore, the higher the efficacy the higher the selective pressure, and the more drastic changes, such as histological transformation, are required to escape the pressure. Therefore, SCLC transformation of ALK ‐positive tumours was more frequently reported related to alectinib than crizotinib treatment, 138 and this finding might be reasonable considering the differences in half maximal inhibitory concentration (IC50) and clinical efficacy between the two agents. As a resistance mechanism, transformation to squamous‐cell carcinoma and epithelial–mesenchymal transition (EMT) has also been reported, although a certain preference for histological changes is suggested according to the driver mutations.…”

Section: Progression and Transformationmentioning

confidence: 95%

Molecular pathology of non‐small cell carcinoma

Yatabe

2023

Histopathology

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Currently, lung cancer is treated by the highest number of therapeutic options and the benefits are based on multiple large‐scale sequencing studies, translational research and new drug development, which has promoted our understanding of the molecular pathology of lung cancer. According to the driver alterations, different characteristics have been revealed, such as differences in ethnic prevalence, median age and alteration patterns. Consequently, beyond traditional chemoradiotherapy, molecular‐targeted therapy and treatment with immune check‐point inhibitors (ICI) also became available major therapeutic options. Interestingly, clinical results suggest that the recently established therapies target distinct lung cancer proportions, particularly between the EGFR/ALK and PD‐1/PD‐L1‐positive subsets, e.g. the kinase inhibitors target driver mutation‐positive tumours, whereas driver mutation‐negative tumours respond to ICI treatment. These therapeutic efficacy‐related differences might be explained by the molecular pathogenesis of lung cancer. Addictive driver mutations promote tumour formation with powerful transformation performance, resulting in a low tumour mutation burden, reduced immune surveillance, and subsequent poor response to ICIs. In contrast, regular tobacco smoke exposure repeatedly injures the proximal airway epithelium, leading to accumulated genetic alterations. In the latter pathway, overgrowth due to alteration and immunological exclusion against neoantigens is initially balanced. However, tumours could be generated from certain clones that outcompete immunological exclusion and outgrow the others. Consequently, this cancer type responds to immune check‐point treatment. These pathogenic differences are explained well by the two‐compartment model, focusing upon the anatomical and functional composition of distinct cellular components between the terminal respiratory unit and the air‐conducting system.

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Section: Progression and Transformationmentioning

confidence: 95%

Molecular pathology of non‐small cell carcinoma

Yatabe

2023

Histopathology

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“…Lineage transformation, recognized as a resistance mechanism to ALK-TKIs, occurs at a low frequency, less than 5%, and is primarily attributed to changes in transcriptional patterns rather than acquiring new genomic mutations in the cells [160]. In cases of resistance to second-generation ALK-TKIs, treatment strategies should be personalized according to the identified resistance mechanisms.…”

Section: Alk and Co-targeting Approachesmentioning

confidence: 99%

Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions

Parvaresh,

Roozitalab,

Golandam

et al. 2024

Biomedicines

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Background and Objective: This review comprehensively explores the intricate landscape of anaplastic lymphoma kinase (ALK), focusing specifically on its pivotal role in non-small cell lung cancer (NSCLC). Tracing ALK’s discovery, from its fusion with nucleolar phosphoprotein (NPM)-1 in anaplastic large cell non-Hodgkin’s lymphoma (ALCL) in 1994, the review elucidates the subsequent impact of ALK gene alterations in various malignancies, including inflammatory myofibroblastoma and NSCLC. Approximately 3–5% of NSCLC patients exhibit complex ALK rearrangements, leading to the approval of six ALK-tyrosine kinase inhibitors (TKIs) by 2022, revolutionizing the treatment landscape for advanced metastatic ALK + NSCLC. Notably, second-generation TKIs such as alectinib, ceritinib, and brigatinib have emerged to address resistance issues initially associated with the pioneer ALK-TKI, crizotinib. Methods: To ensure comprehensiveness, we extensively reviewed clinical trials on ALK inhibitors for NSCLC by 2023. Additionally, we systematically searched PubMed, prioritizing studies where the terms “ALK” AND “non-small cell lung cancer” AND/OR “NSCLC” featured prominently in the titles. This approach aimed to encompass a spectrum of relevant research studies, ensuring our review incorporates the latest and most pertinent information on innovative and alternative therapeutics for ALK + NSCLC. Key Content and Findings: Beyond exploring the intricate details of ALK structure and signaling, the review explores the convergence of ALK-targeted therapy and immunotherapy, investigating the potential of immune checkpoint inhibitors in ALK-altered NSCLC tumors. Despite encouraging preclinical data, challenges observed in trials assessing combinations such as nivolumab-crizotinib, mainly due to severe hepatic toxicity, emphasize the necessity for cautious exploration of these novel approaches. Additionally, the review explores innovative directions such as ALK molecular diagnostics, ALK vaccines, and biosensors, shedding light on their promising potential within ALK-driven cancers. Conclusions: This comprehensive analysis covers molecular mechanisms, therapeutic strategies, and immune interactions associated with ALK-rearranged NSCLC. As a pivotal resource, the review guides future research and therapeutic interventions in ALK-targeted therapy for NSCLC.

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“…Through the lens of ALK-positive lung cancer, we also take a deep dive into topics broadly relevant to oncogene-addicted tumors, including: (I) the biology and targeting of brain metastases ( 24 ); (II) lineage plasticity (e.g., epithelial mesenchymal transition and histologic transformation) ( 25 ); and (III) the barriers in harnessing immune responses [i.e., lack of benefit from anti-PD(L)1 immune checkpoint inhibition] and future directions for leveraging immunotherapy (e.g., ALK-directed vaccine approaches, adoptive cell therapy, oncolytic viruses) ( 26 ). Each of these topics currently represents a major scientific and therapeutic bottleneck, relevant across oncogene-addicted lung cancers, and we anticipate that breakthroughs therein will move the needle on patient outcomes.…”

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confidence: 99%