Beyond EGFR, ALK and ROS1: Current evidence and future perspectives on newly targetable oncogenic drivers in lung adenocarcinoma

Lamberti, Giuseppe; Andrini, Elisa; Sisi, Monia; Rizzo, Alessandro; Parisi, Claudia; Federico, Alessandro Di; Gelsomino, Francesco; Ardizzoni, Andrea

doi:10.1016/j.critrevonc.2020.103119

Cited by 110 publications

(79 citation statements)

References 204 publications

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“…), increasing numbers of rare molecular changes in oncogenic drivers (including HER2, MET, and RET) have been identified (Yu et al, 2018). Specific tyrosine kinase inhibitors targeting these genomic changes have shown improved patient survival and satisfactory biological activity, mostly in phase III clinical trials, which has led the US Food and Drug Administration to accelerate the approval of some of these drugs (Lamberti et al, 2020). However, the 5 year survival rate has only increased by 5% in the past 20 years (Johnson et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Prognostic Signature for Lung Adenocarcinoma Patients Based on Cell-Cycle-Related Genes

Jiang

Liao

et al. 2021

Front. Cell Dev. Biol.

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ObjectiveTo screen lung adenocarcinoma (LUAC)-specific cell-cycle-related genes (CCRGs) and develop a prognostic signature for patients with LUAC.MethodsThe GSE68465, GSE42127, and GSE30219 data sets were downloaded from the GEO database. Single-sample gene set enrichment analysis was used to calculate the cell cycle enrichment of each sample in GSE68465 to identify CCRGs in LUAC. The differential CCRGs compared with LUAC data from The Cancer Genome Atlas were determined. The genetic data from GSE68465 were divided into an internal training group and a test group at a ratio of 1:1, and GSE42127 and GSE30219 were defined as external test groups. In addition, we combined LASSO (least absolute shrinkage and selection operator) and Cox regression analysis with the clinical information of the internal training group to construct a CCRG risk scoring model. Samples were divided into high- and low-risk groups according to the resulting risk values, and internal and external test sets were used to prove the validity of the signature. A nomogram evaluation model was used to predict prognosis. The CPTAC and HPA databases were chosen to verify the protein expression of CCRGs.ResultsWe identified 10 LUAC-specific CCRGs (PKMYT1, ETF1, ECT2, BUB1B, RECQL4, TFRC, COCH, TUBB2B, PITX1, and CDC6) and constructed a model using the internal training group. Based on this model, LUAC patients were divided into high- and low-risk groups for further validation. Time-dependent receiver operating characteristic and Cox regression analyses suggested that the signature could precisely predict the prognosis of LUAC patients. Results obtained with CPTAC, HPA, and IHC supported significant dysregulation of these CCRGs in LUAC tissues.ConclusionThis prognostic prediction signature based on CCRGs could help to evaluate the prognosis of LUAC patients. The 10 LUAC-specific CCRGs could be used as prognostic markers of LUAC.

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Section: Introductionmentioning

confidence: 99%

Prognostic Signature for Lung Adenocarcinoma Patients Based on Cell-Cycle-Related Genes

Jiang

Liao

et al. 2021

Front. Cell Dev. Biol.

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“…Mesenchymal-epithelial transition factor (MET)-activating alterations, including overexpression (15-70%), amplification (2-5%), and exon 14 (METex14) skipping mutations (3-4%), are oncogenic drivers in 5-9% of newly diagnosed non-squamous NSCLC [5,6]. MET amplification is also responsible for the 10-20% of the acquired resistance, especially to EGFR inhibitors, but also to ALK inhibitors, although METex14 mutations are also emerging as a resistance mechanism [7,8].…”

Section: Met 21 Epidemiologymentioning

confidence: 99%

“…MET TKIs are the principal MET-targeted drugs for METex14 mutations and they are divided into non-selective (multi-targeted) TKIs and the more efficient selective TKIs. Among the first ones, the most studied TKI with positive results was crizotinib, whereas the second ones (e.g., capmatinib, tepotinib, savolitinib) have recently provided encouraging data [6] (Table 1). Due to the great number of MET inhibitors currently under investigation, in this review we focused on the Phase II-III trials of selective TKIs.…”

Section: Met As Primary Oncogenic Drivermentioning

confidence: 99%

Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

Rebuzzi

Zullo

Rossi

et al. 2021

IJMS

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In the scenario of systemic treatment for advanced non-small cell lung cancer (NSCLC) patients, one of the most relevant breakthroughs is represented by targeted therapies. Throughout the last years, inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-Ros oncogene 1 (ROS1), and V-raf murine sarcoma viral oncogene homolog B (BRAF) have been approved and are currently used in clinical practice. However, other promising molecular drivers are rapidly emerging as therapeutic targets. This review aims to cover the molecular alterations with a potential clinical impact in NSCLC, including amplifications or mutations of the mesenchymal–epithelial transition factor (MET), fusions of rearranged during transfection (RET), rearrangements of the neurotrophic tyrosine kinase (NTRK) genes, mutations of the Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), as well as amplifications or mutations of human epidermal growth factor receptor 2 (HER2). Additionally, we summarized the current status of targeted agents under investigation for such alterations. This revision of the current literature on emerging molecular targets is needed as the evolving knowledge on novel actionable oncogenic drivers and targeted agents is expected to increase the proportion of patients who will benefit from tailored therapeutic approaches.

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“…Mouse double minute homolog (MDM2/MDM4) amplification and epidermal growth factor receptor (EGFR) alterations were indicated as genomic markers of increased risk of hyperprogression [19,28]. Furthermore, patients with oncogene-addicted NSCLC, e.g., ALK, EGFR and STK11, did not benefit from IC blockade therapy, probably because of the "cold" nature of these tumors [29][30][31][32][33][34]. Hyperprogression was also associated with elevated serum lactate dehydrogenase (LDH) concentration [10,12,15,35].…”

Section: Clinical Evidence Of Hyperprogression and Associated Factorsmentioning

confidence: 99%

IFN-γ and CD38 in Hyperprogressive Cancer Development

Angelicola

Ruzzi

Landuzzi

et al. 2021

Cancers

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Immune checkpoint inhibitors (ICIs) improve the survival of patients with multiple types of cancer. However, low response rates and atypical responses limit their success in clinical applications. The paradoxical acceleration of tumor growth after treatment, defined as hyperprogressive disease (HPD), is the most difficult problem facing clinicians and patients alike. The mechanisms that underlie hyperprogression (HP) are still unclear and controversial, although different factors are associated with the phenomenon. In this review, we propose two factors that have not yet been demonstrated to be directly associated with HP, but upon which it is important to focus attention. IFN-γ is a key cytokine in antitumor response and its levels increase during ICI therapy, whereas CD38 is an alternative immune checkpoint that is involved in immunosuppressive responses. As both factors are associated with resistance to ICI therapy, we have discussed their possible involvement in HPD with the conclusion that IFN-γ may contribute to HP onset through the activation of the inflammasome pathway, immunosuppressive enzyme IDO1 and activation-induced cell death (AICD) in effector T cells, while the role of CD38 in HP may be associated with the activation of adenosine receptors, hypoxia pathways and AICD-dependent T-cell depletion.

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Beyond EGFR, ALK and ROS1: Current evidence and future perspectives on newly targetable oncogenic drivers in lung adenocarcinoma

Cited by 110 publications

References 204 publications

Prognostic Signature for Lung Adenocarcinoma Patients Based on Cell-Cycle-Related Genes

Prognostic Signature for Lung Adenocarcinoma Patients Based on Cell-Cycle-Related Genes

Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

IFN-γ and CD38 in Hyperprogressive Cancer Development

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