Concurrent RB1 and TP53 Alterations Define a Subset of EGFR-Mutant Lung Cancers at risk for Histologic Transformation and Inferior Clinical Outcomes

Offin, Michael; Chan, Joseph M.; Tenet, Megan; Rizvi, Hira; Shen, Ronglai; Riely, Gregory J.; Rekhtman, Natasha; Daneshbod, Yahya; Quintanal-Villalonga, Àlvaro; Penson, A.; Hellmann, Matthew D.; Arcila, Maria E.; Ladanyi, Marc; Pe’er, Dana; Kris, Mark G.; Rudin, Charles M.; Yu, Helena A.

doi:10.1016/j.jtho.2019.06.002

Cited by 273 publications

(251 citation statements)

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“…Alteration of RB1 and/or TP53 is likely to increase the likelihood that EGFR-mutant adenocarcinoma will relapse as an SCLC variant. These variants have distinct therapeutic sensitivities and are generally lethal because they rapidly develop resistance (Offin et al, 2019). Thus, routine determination of RB1/TP53 mutation status merits consideration, especially if therapeutic intervention can prevent or delay SCLC transformation.…”

Section: Use Of Bcl-2 Inhibitorsmentioning

confidence: 99%

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

et al. 2020

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Somatic alterations in the epidermal growth factor receptor gene (EGFR) result in aberrant activation of kinase signaling and occur in ∼15% of non-small cell lung cancers (NSCLC). Patients diagnosed with EGFR-mutant NSCLC have good initial clinical response to EGFR tyrosine kinase inhibitors (EGFR TKIs), yet tumor recurrence is common and quick to develop. Mechanisms of acquired resistance to EGFR TKIs have been studied extensively over the past decade. Great progress has been made in understanding two major routes of therapeutic failure: additional genomic alterations in the EGFR gene and activation of alternative kinase signaling (so-called "bypass activation"). Several pharmacological agents aimed at overcoming these modes of EGFR TKI resistance are FDA-approved or under clinical development. Phenotypic transformation, a less common and less well understood mechanism of EGFR TKI resistance is yet to be addressed in the clinic. In the context of acquired EGFR TKI resistance, phenotypic transformation encompasses epithelial to mesenchymal transition (EMT), transformation of adenocarcinoma of the lung (LUAD) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). SCLC transformation, or neuroendocrine differentiation, has been linked to inactivation of TP53 and RB1 signaling. However, the exact mechanism that permits lineage switching needs further investigation. Recent reports indicate that LUAD and SCLC have a common cell of origin, and that trans-differentiation occurs under the right conditions. Options for therapeutic targeting of EGFR-mutant SCLC are limited currently to conventional genotoxic chemotherapy. Similarly, the basis of EMT-associated resistance is not clear. EMT is a complex process that can be characterized by a spectrum of intermediate states with diverse expression of epithelial and mesenchymal factors. In the context of acquired resistance to EGFR TKIs, EMT frequently co-occurs with bypass activation, making it challenging to determine the exact contribution of EMT to therapeutic failure. Reversibility of EMT-associated resistance points toward its epigenetic origin, with additional adjustments, such as genetic alterations and bypass activation, occurring later during disease progression. This review will discuss the mechanistic basis for EGFR TKI resistance linked to phenotypic transformation, as well as challenges and opportunities in addressing this type of targeted therapy resistance in EGFR-mutant NSCLC.

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Section: Use Of Bcl-2 Inhibitorsmentioning

confidence: 99%

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

et al. 2020

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“…Paste the sequence and click submit to get the result of each sequence. In the result, the first five relevant descriptions are considered [9]. Blastp was used to explore the protein function as well as to find the homologous protein of the sequences as shown in the (Table 1.0) below and the pie chart was plotted as shown in (Figure 1.1.0).…”

Section: Resultsmentioning

confidence: 99%

“…The functions of 1350 protein sequences with high confidence were assigned. The result in (Figure 1.1 oxidoreductases, lyases, kinase and also ligase [9].…”

Section: Discussionmentioning

confidence: 95%

“…One of the best and initial steps to explore and identify the homology shared between the proteins that may lead to the strong function prediction with the help of the advance bioinformatics tools for the sequences. This study have successfully characterized 1350 HPs of P.aeruginosa by using various computational bioinformatics tools [9].These analyses of sequences of all the HPS was carried out by using Basic Local Alignment Search Tool Protein (Blastp), Protein Family (pfam), Conserved Domain Database (CDD), The Integrative Protein Signature Database (interproScan) and also Simple Modular Architecture Research Tool and Database (SMART). After that the HPs was precisely defined as the subcellular localization, physiochemical properties as well as which family they belong to by using Expasy Protein Parameters Tools (Expasy's ProtParam), Signal Peptide Sequence Analysis (SignalP), Subcellular Localization Predictive System(CELLO), Prediction of Subcellular Localization of Bacterial Proteins (PSLpred), Predictions of Transmembrane Helices and Topology of Protein (HMMTOP) and last but not least is Prediction of Transmembrane Helices based on the Hidden Markov Model (TMHMM) [10].…”

Section: Introductionmentioning

confidence: 99%

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Structural and Functional Prediction of the Hypothetical Proteins from Pseudomonas Aeruginosa PA7

2019

AIDT

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Background & Aim: Pseudomonas aeruginosa is the most frequently isolated bacterium among those gram negative rods that are obligated aerobes. It is one of the important opportunistic human pathogens, causing severe chronic respiratory infection in patient with underlying conditions such as cystic fibrosis (CF) or bronchiectasis. The emergence of multi-drug resistance Pseudomonas aeruginosa strain in clinically isolated demands the development of better or new drugs against this pathogen. The study is to assign a precise function to hypothetical protein (HPs), whose functions are unknown. Materials and Methods: With the help of various bioinformatics tools, the extensive functional analysis of these hypothetical proteins was performed. This study combines a number of bioinformatics tools including Blastp, Pfam, InterProScan, SMART, PSLPred, CELLO, Signal Peptide, Expasy’s ProtParam tool, VirulenPred, VicmPred to gain information about the conserved regions, families, pathways, interactions, localizations and virulence related to particular protein. Result: The hypothetical proteins present in Pseudomonas Aeruginosa PA7 genome was extensively analyzed and annotated, out of 1350 hypothetical proteins, 25 proteins are catalytic domains, 31 proteins are enzymes, 46 proteins are integral membrane proteins, 72 proteins are transporters, 104 proteins are binding proteins, 404 proteins sequences contain a domain of unknown function (DUF), and 540 proteins cannot be functionally determined by any of the tools. Conclusion: Better understanding of the mechanism of pathogenesis and in finding novel therapeutic targets for Pseudomonas aeruginosa.

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“…Histologic transformation of NSCLC to SCLC has already been recognized as a crucial mechanism of acquired resistance to EGFR-or ALK-TKI in EGFR-mutated [49,57] or ALK+ adenocarcinomas [58]. Cooccurring mutations of the tumor-suppressor genes TP53 and RB1 (RB transcriptional corepressor 1) could be observed in over 75% of patients with SCLC [59,60]. Patients with EGFR/RB1/TP53-mutant lung cancers represented approximately 5% of EGFR-mutant lung cancers and were at much higher risk for SCLC transformation than those without baseline TP53 and RB1 alterations [61].…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis

Qin

Hou

et al. 2020

Preprint

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Background The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)-or anaplastic lymphoma kinase (ALK)-mutated advanced non-smallcell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments.Methods Eligible studies were identified by searching the online databases PubMed, Embase, Medline,The Cochrane library and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between TP53 mutation status and prognosis of patients.This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. ResultsIn total, 15 studies with 1342 patients were included for final analysis. Overall, concurrent TP53 mutation was associated with unfavorable progression-free survival (PFS) (HR=1.88, 95%CI:1.59-2.23, p<0.001, I2=0.0%, P=0.792) and overall survival (OS) (HR=1.92, 95%CI: 1.55-2.38, p<0.001, I2=0.0%, P=0.515). Subgroup analysis based on type of targeted therapy (EGFR-TKIs or ALK-TKIs, pathological type of cancer (adenocarcinoma only or all NSCLC subtypes) and line of treatment (first-line only or all lines) all showed that TP53 mutations was associated with shorter survivals of patients with EGFR-TKIs or ALK-TKIs treatments. Particularly, in patients with first-line EGFR-TKIs treatment, significantly poorer prognosis was observed in patients with TP53 concurrent mutations (pooled HR for PFS: 1.69, 95% CI 1.25-2.27, P<0.001, I2=0.0%, P=0.473; pooled HR for OS:1.94, 95% CI 1.36-2.76, P<0.001, I2=0.0%, P=0.484). Begg's funnel plots and Egger's tests indicated no significant publication bias in this study.Conclusions This meta-analysis indicated that concurrent TP53 mutations was a negative prognostic factor and associated with poorer outcomes of patients with EGFR-TKIs or ALK-TKIs treatments in advanced NSCLC. In addition, our study provided evidence that TP53 mutations might be involved in primary resistance to EGFR-TKIs treatments in patients with sensitive EGFR mutations in advanced

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Concurrent RB1 and TP53 Alterations Define a Subset of EGFR-Mutant Lung Cancers at risk for Histologic Transformation and Inferior Clinical Outcomes

Cited by 273 publications

References 30 publications

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

Structural and Functional Prediction of the Hypothetical Proteins from Pseudomonas Aeruginosa PA7

Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis

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