scholarly journals Targeted Therapy in Advanced and Metastatic Non-Small Cell Lung Cancer. An Update on Treatment of the Most Important Actionable Oncogenic Driver Alterations

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 804
Author(s):  
David König ◽  
Spasenija Savic Prince ◽  
Sacha I. Rothschild
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
New Drugs ◽  
Small Cell Lung ◽  
Comprehensive Overview ◽  
Kras Mutations ◽  
Anaplastic Lymphoma ◽  
Oncogenic Driver

Due to groundbreaking developments and continuous progress, the treatment of advanced and metastatic non-small cell lung cancer (NSCLC) has become an exciting, but increasingly challenging task. This applies, in particular, to the subgroup of NSCLC with oncogenic driver alterations. While the treatment of epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged NSCLC with various tyrosine kinase inhibitors (TKIs) is well-established, new targets have been identified in the last few years and new TKIs introduced in clinical practice. Even for KRAS mutations, considered for a long time as an “un-targetable” alteration, promising new drugs are emerging. The detection and in-depth molecular analysis of resistance mechanisms has further fueled the development of new therapeutic strategies. The objective of this review is to give a comprehensive overview on the current landscape of targetable oncogenic alterations in NSCLC.

scholarly journals The development of potential targets in the treatment of non-small cell lung cancer

2016 ◽  
Vol 11 (1) ◽  
pp. 225-231
Author(s):  
Jimin Zhang ◽  
Zhihui Lin
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Anaplastic Lymphoma

AbstractThe oncogenic driver mutations have been found that not only have potential sensitivity to epidermal growth factor receptor but also can inhibit anaplastic lymphoma kinase tyrosine kinase; more and more interest has been evoked in discovering additional targets to non-small cell lung cancer (NSCLC). Recently, many novel underlying oncogenic gene alterations have been identified, such as HER2 insertions, BRAF mutations, PIK3 mutations, FGFR1 amplifications, DDR2 mutations, KRAS mutations, MET amplification, ROS1 rearrangements, ALK rearrangements, and RET rearrangements. In this review, we will discuss the discovery of these potential targets and the application of each in NSCLC and of small molecular inhibitors on these potential targets.

scholarly journals The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Yue Pan ◽  
Chao Deng ◽  
Zhenhua Qiu ◽  
Chenghui Cao ◽  
Fang Wu
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Resistance Mechanisms ◽  
Small Cell ◽  
New Drugs ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma

Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance.

scholarly journals New Target Therapies in Advanced Non-Small Cell Lung Cancer: A Review of the Literature and Future Perspectives

2020 ◽  
Vol 9 (11) ◽  
pp. 3543
Author(s):  
Ramon Andrade de Mello ◽  
Nathália Moisés Neves ◽  
Hakaru Tadokoro ◽  
Giovanna Araújo Amaral ◽  
Pedro Castelo-Branco ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
New Drugs ◽  
Cytotoxic Agents ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Anaplastic Lymphoma ◽  
Target Therapies

Introduction: Lung cancer (LC) is the most common neoplasm worldwide, and 85% of these tumors are classified as non-small cell lung cancer (NSCLC). LC treatment was initially restricted to cytotoxic chemotherapy—platinum compounds associated with 3rd generation cytotoxic agents (paclitaxel, gemcitabine, pemetrexed) and, more recently, with monoclonal antibodies (bevacizumab, ramucirumab). Advancements in treatment are correlated with prolonged overall survival (OS). Current advances are focused on target therapies. Target agents: Anti-epidermal growth factor receptor (EGFR) therapy consists of 1st and 2nd generation tyrosine kinase inhibitors (TKIs such as erlotinib, afatinib). In 60% of cases, resistance to these TKIs occurs due to T790M mutation in EGFR, which is overcome 3rd generation drugs (osimertinib). Anaplastic lymphoma kinase (ALK) is the target for drugs such as crizotinib, alectinib, ceritinib. Programmed death 1 (PD-1) and its ligand serve as targets for immunotherapy agents such as pembrolizumab, nivolumab, atezolizumab. Discussion: Challenges in NSCLC treatment include resistance to 3rd generation TKIs, the high cost of ALK inhibitors, and the need for further research on new drugs.

scholarly journals The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer

2020 ◽  
Vol 13 (12) ◽  
pp. 474
Author(s):  
Valerio Gristina ◽  
Maria La Mantia ◽  
Federica Iacono ◽  
Antonio Galvano ◽  
Antonio Russo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Fusion Gene ◽  
Small Cell ◽  
Small Cell Lung ◽  
Rapid Improvement ◽  
Comprehensive Overview ◽  
Anaplastic Lymphoma ◽  
Alk Positive

The treatment of metastatic non-small cell lung cancer (NSCLC) has undergone a paradigm shift over the last decade. Better molecular characterization of the disease has led to the rapid improvement of personalized medicine and the prompt delivery of targeted therapies to patients with NSCLC. The discovery of the EML4-ALK fusion gene in a limited subset of patients affected by NSCLC and the subsequent clinical development of crizotinib in 2011 has been an impressive milestone in lung cancer research. Unfortunately, acquired resistances regularly develop, hence disease progression occurs. Afterward, modern tyrosine kinase inhibitors (TKIs), such as ceritinib, alectinib, brigatinib, and lorlatinib, have been approved by the Food and Drug Administration (FDA) for the management of anaplastic lymphoma kinase (ALK)-positive NSCLCs. Several compounds are currently under investigation to achieve the optimal strategy of therapy. Additionally, the results of ongoing clinical trials with novel-generation TKI will provide more evidence on the best sequence in the treatment of ALK-positive NSCLC patients. In this review, we provide a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized.

Landmark Studies of Targeted Therapies for Advanced Non-Small Cell Lung Cancer: A Guide for Pulmonologists

2020 ◽  
Vol 16 (1) ◽  
pp. 5-10
Author(s):  
Adrien Costantini ◽  
Theodoros Katsikas ◽  
Clementine Bostantzoglou
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Standard Of Care ◽  
Genetic Alterations ◽  
Small Cell ◽  
Extensive Literature ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Mutational Status

Over the past decade, major breakthroughs in the understanding of lung cancer histology and mutational pathways have radically changed diagnosis and management. More specifically, in non-small cell lung cancer (NSCLC), tumour characterisation has shifted from differentiating based solely on histology to characterisation that includes genetic profiling and mutational status of Epidermal Growth Factor (EGFR), Anaplastic Lymphoma Kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF. These genetic alterations can be targeted by specific drugs that result in improved progression-free survival, as well as higher response rates and are currently standard of care for NSCLC patients harbouring these mutations. In this a narrative, non-systematic review we aim to handpick through the extensive literature and critically present the ground-breaking studies that lead to the institution of tailored treatment options as the standard of care for the main targetable genetic alterations.

scholarly journals Current Status and Future Perspectives of Liquid Biopsy in Small Cell Lung Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 48
Author(s):  
Patricia Mondelo-Macía ◽  
Jorge García-González ◽  
Luis León-Mateos ◽  
Adrián Castillo-García ◽  
Rafael López-López ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Small Cell ◽  
New Drugs ◽  
Current Status ◽  
Small Cell Lung ◽  
Tumor Biopsy ◽  
Future Utility

Approximately 19% of all cancer-related deaths are due to lung cancer, which is the leading cause of mortality worldwide. Small cell lung cancer (SCLC) affects approximately 15% of patients diagnosed with lung cancer. SCLC is characterized by aggressiveness; the majority of SCLC patients present with metastatic disease, and less than 5% of patients are alive at 5 years. The gold standard of SCLC treatment is platinum and etoposide-based chemotherapy; however, its effects are short. In recent years, treatment for SCLC has changed; new drugs have been approved, and new biomarkers are needed for treatment selection. Liquid biopsy is a non-invasive, rapid, repeated and alternative tool to the traditional tumor biopsy that could allow the most personalized medicine into the management of SCLC patients. Circulating tumor cells (CTCs) and cell-free DNA (cfDNA) are the most commonly used liquid biopsy biomarkers. Some studies have reported the prognostic factors of CTCs and cfDNA in SCLC patients, independent of the stage. In this review, we summarize the recent SCLC studies of CTCs, cfDNA and other liquid biopsy biomarkers, and we discuss the future utility of liquid biopsy in the clinical management of SCLC.

scholarly journals Circulating tumor cell copy-number heterogeneity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Marianne Oulhen ◽  
Patrycja Pawlikowska ◽  
Tala Tayoun ◽  
Marianna Garonzi ◽  
Genny Buson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Copy Number ◽  
Epithelial To Mesenchymal Transition ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mesenchymal Transition ◽  
Anaplastic Lymphoma

AbstractGatekeeper mutations are identified in only 50% of the cases at resistance to Anaplastic Lymphoma Kinase (ALK)-tyrosine kinase inhibitors (TKIs). Circulating tumor cells (CTCs) are relevant tools to identify additional resistance mechanisms and can be sequenced at the single-cell level. Here, we provide in-depth investigation of copy number alteration (CNA) heterogeneity in phenotypically characterized CTCs at resistance to ALK-TKIs in ALK-positive non-small cell lung cancer. Single CTC isolation and phenotyping were performed by DEPArray or fluorescence-activated cell sorting following enrichment and immunofluorescence staining (ALK/cytokeratins/CD45/Hoechst). CNA heterogeneity was evaluated in six ALK-rearranged patients harboring ≥ 10 CTCs/20 mL blood at resistance to 1st and 3rd ALK-TKIs and one presented gatekeeper mutations. Out of 82 CTCs isolated by FACS, 30 (37%) were ALK+/cytokeratins-, 46 (56%) ALK-/cytokeratins+ and 4 (5%) ALK+/cytokeratins+. Sequencing of 43 CTCs showed highly altered CNA profiles and high levels of chromosomal instability (CIN). Half of CTCs displayed a ploidy >2n and 32% experienced whole-genome doubling. Hierarchical clustering showed significant intra-patient and wide inter-patient CTC diversity. Classification of 121 oncogenic drivers revealed the predominant activation of cell cycle and DNA repair pathways and of RTK/RAS and PI3K to a lower frequency. CTCs showed wide CNA heterogeneity and elevated CIN at resistance to ALK-TKIs. The emergence of epithelial ALK-negative CTCs may drive resistance through activation of bypass signaling pathways, while ALK-rearranged CTCs showed epithelial-to-mesenchymal transition characteristics potentially contributing to ALK-TKI resistance. Comprehensive analysis of CTCs could be of great help to clinicians for precision medicine and resistance to ALK-targeted therapies.

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