ALK rearrangements: Biology, detection and opportunities of therapy in non-small cell lung cancer

Rosas, Gina; Ruiz, Rossana; Araujo, Jhajaira M.; Pinto, Joseph A.; López, Luis Alberto Moreno

doi:10.1016/j.critrevonc.2019.02.006

Cited by 43 publications

(28 citation statements)

References 68 publications

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“…The therapeutic landscape of non-small-cell lung cancer (NSCLC) harboring oncogenic driver alterations has revolutionized by the introduction of tyrosine kinase targeted inhibitors (TKIs), such as Epidermal Growth Factor Receptor (EGFR) [1], and Anaplastic Lymphoma Kinase (ALK) TKIs [2]. Currently, there are several biomarker-defined patient subgroups, in which treatment with specific TKIs have superior clinical outcomes compared to standard conventional cytotoxic chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

“…The L858R mutation and exon 19 deletion in EGFR as well as Anaplastic Lymphoma Kinase (ALK) translocation have been demonstrated as reliable biomarkers for the response to EGFR [1] and ALK inhibitors [2], respectively. Nonetheless, in most cases, acquired resistance against TKIs occurs after an average of one year, leading to renewed tumor growth and progression, suggesting specific pathogenetic mechanisms, e.g., c-Met amplification [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

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The Role of c-Met as a Biomarker and Player in Innate and Acquired Resistance in Non-Small-Cell Lung Cancer: Two New Mutations Warrant Further Studies

et al. 2019

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The c-Met receptor is a therapeutically actionable target in non-small-cell lung cancer (NSCLC), with one approved drug and several agents in development. Most suitable biomarkers for patient selection include c-Met amplification and exon-14 skipping. Our retrospective study focused on the frequency of different c-Met aberrations (overexpression, amplification and mutations) in 153 primary, therapy-naïve resection samples and their paired metastases, from Biobank@UZA. Furthermore, we determined the correlation of c-Met expression with clinicopathological factors, Epidermal Growth Factor Receptor (EGFR)-status and TP53 mutations. Our results showed that c-Met expression levels in primary tumors were comparable to their respective metastases. Five different mutations were detected by deep sequencing: three (E168D, S203T, N375S) previously described and two never reported (I333T, G783E). I333T, a new mutation in the Sema(phorin) domain of c-Met, might influence the binding of antibodies targeting the HGF-binding domain, potentially causing innate resistance. E168D and S203T mutations showed a trend towards a correlation with high c-Met expression (p = 0.058). We found a significant correlation between c-MET expression, EGFR expression (p = 0.010) and EGFR mutations (p = 0.013), as well as a trend (p = 0.057) with regards to TP53 mutant activity. In conclusion this study demonstrated a strong correlation between EGFR mutations, TP53 and c-Met expression in therapy-naïve primary resection samples. Moreover, we found two new c-Met mutations that warrant further studies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Role of c-Met as a Biomarker and Player in Innate and Acquired Resistance in Non-Small-Cell Lung Cancer: Two New Mutations Warrant Further Studies

et al. 2019

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“…S tím souvisí dramatický rozvoj možností systémové léčby v posledním desetiletí, protože se často jedná o alterace ovlivnitelné cílenou léčbou (targetable mutations). U pacientů s aktivačními mutacemi genu pro receptor epidermálního růstového faktoru (epidermal growth factor receptor -EGFR) nebo přestavbou ALK či ROS1 bylo dosaženo výrazného zlepšení léčebných výsledků [3,4]. Mezi další terapeutické cíle patří B-RAF, c-met, RET a další [5][6][7].…”

Section: úVodunclassified

Uncommon EGFR Mutations in Non-Small Cell Lung Cancer and Their Impact on the Treatment

Bílek¹,

Holánek²,

Berkovcová³

et al. 2019

Klin Onkol

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Východiska: Mutace genu pro receptor epidermálního růstového faktoru (epidermal growth factor receptor-EGFR) hrají důležitou roli v patogenezi nemalobuněčného karcinomu plic. Protože se jedná o alterace často ovlivnitelné cílenou léčbou, představuje jejich detekce součást běžné klinické praxe. U pacientů s aktivačními mutacemi EGFR bylo dosaženo výrazného zlepšení léčebných výsledků pomocí cílené léčby tyrozinkinázovými inhibitory. Dia gnostickým standardem mutací EGFR jsou v současné době metody založené na polymerázové řetězové reakci, zejména kvantitativní polymerázová řetězová reakce v reálném čase. V posledních letech roste význam sekvenování nové generace. EGFR obsahuje čtyři domény: extracelulární s vazebným místem ligandu, transmembránovou doménu, cytoplazmatickou tyrozinkinázovou katalytickou doménu a C-terminální doménu. Klíčové struktury tyrozinkinázové domény zodpovědné za aktivaci a přenos signálu jsou kódovány v rámci exonů 18-21 na 7. chromozomu. Mutace EGFR jsou vysoce heterogenní. Asi 90 % mutací EGFR tvoří delece exonu 19 a bodová mutace L858R v exonu 21. Jsou označovány za "klasické" mutace. Přibližně 10% podíl z celkového počtu mutací připadá na méně časté alterace genu pro EGFR. Vzhledem k nízké incidenci nemalobuněčného karcinomu plic s méně častými mutacemi je stále třeba nových informací o jejich prediktivním významu. Většinu dosavadních dat o méně častých mutacích tvoří retrospektivní analýzy a hodnocení menších souborů. Cíl: Cílem tohoto přehledového článku je shrnout možnosti dia gnostiky a léčby nemalobuněčného karcinomu plic s méně častými mutacemi EGFR. Klíčová slova nemalobuněčný karcinom plic-receptor pro epidermální růstový faktor-tyrozinkinázové inhibitory-cílená léčba-mutace EGFR Práce byla podpořena MŠMT-NPU I-LO1413 a MZ ČR-RVO (MOÚ, 00209805). This work was supported by the MEYS-NPS I-LO1413 and MH CR-DRO (MMCI, 00209805). Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do bi omedicínských časopisů. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

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“…Thus, for decades, cancer research has aimed to find driver mutations of malignant cells, which could be targeted for more selective and effective therapy. [6][7][8][9][10] Currently, upon NSCLC diagnosis, mutational testing for epidermal growth factor receptor-1 (EGFR), anaplastic lymphoma kinase (ALK), protooncogene tyrosine-protein kinase (ROS-1), and serine/threonine-protein kinase B-Raf (BRAF) should be performed in order to start first-line therapy with a targeted agent instead of chemotherapy. 5 Another breakthrough in recent years has been immunotherapeutic treatment with immune checkpoint inhibitors, which were developed to counteract the immunosuppressive effects of the programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway and to activate the immune system for defense against malignant cells.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of immune checkpoint inhibitors in patients with advanced non–small cell lung cancer (NSCLC): a systematic literature review

et al. 2020

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Background: Therapeutic strategies with immune checkpoint inhibitors (ICIs) counteract the immunosuppressive effects of programmed cell death protein-1 (PD-1) and ligand-1 (PD-L1). ICI treatment has emerged in first-and second-line therapy of non-small cell lung cancer (NSCLC). As immunotherapeutic treatment with ICIs is a dynamic field where new drugs and combinations are constantly evaluated, we conducted an up-to-date systematic review on comparative efficacy and safety in patients with advanced NSCLC. Methods: We searched PubMed up to February 2020 and Embase, CENTRAL, and clinical trial registries up to August 2018. Additionally, we checked reference lists. We dually screened titles, abstracts and, subsequently, full-texts for eligibility. Two reviewers assessed the risk of bias and graded the certainty of evidence following GRADE (Grading of Recommendations Assessment, Development and Evaluation). For second-line therapy, we performed random-effects meta-analyses. Due to considerable clinical heterogeneity, we reported first-line results narratively. Results: Of 1497 references, we identified 22 relevant publications of 16 studies. For first-line therapy, a combination of an ICI with chemotherapy improved progression-free survival and overall survival compared to chemotherapy but increased the risk of serious adverse events. Single-agent pembrolizumab increased overall and progression-free survival in patients with PD-L1 expression of ≥50% and resulted in less TRAE than chemotherapy. Compared to placebo, maintenance therapy with durvalumab increased overall and progression-free survival at the downside of higher risk of TRAE. For second-line therapy, a random-effects metaanalysis yielded a statistically significantly improved overall survival (OS) and progression-free survival (PFS) for ICIs compared to docetaxel (HR 0.69; 95% CI: 0.63-0.75 for OS; HR 0.85; 95% CI: 0.77 − 0.93 for PFS; 6 studies, 3478 patients; median OS benefit in months: 2.4 to 4.2). In meta-analysis, risk of any treatment-related adverse events of any grade was lower for ICI than docetaxel as second-line therapy (RR 0.76, 95% CI: 0.73-0.79; 6 studies, 3763 patients). Conclusion: In first-line therapy of patients with advanced NSCLC, ICI is effective when combined with chemotherapy not depending on PD-L1 expression, or as monotherapy in high PD-L1 expressing tumors. For second-line therapy, single-agent ICI improves efficacy and safety compared to docetaxel.

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ALK rearrangements: Biology, detection and opportunities of therapy in non-small cell lung cancer

Cited by 43 publications

References 68 publications

The Role of c-Met as a Biomarker and Player in Innate and Acquired Resistance in Non-Small-Cell Lung Cancer: Two New Mutations Warrant Further Studies

The Role of c-Met as a Biomarker and Player in Innate and Acquired Resistance in Non-Small-Cell Lung Cancer: Two New Mutations Warrant Further Studies

Uncommon EGFR Mutations in Non-Small Cell Lung Cancer and Their Impact on the Treatment

Efficacy and safety of immune checkpoint inhibitors in patients with advanced non–small cell lung cancer (NSCLC): a systematic literature review

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