Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids

10.3791/63039 ◽  
2021 ◽  
Author(s):  
Dora Barbosa Rabago ◽  
Collin M. Blakely ◽  
Franziska Haderk ◽  
Trever G. Bivona
Keyword(s):  
Targeted Therapies ◽  
Nsclc Patient ◽  
Egfr Mutant

A review of Osimertinib in NSCLC and pharmacist role in NSCLC patient care

2020 ◽  
Vol 26 (6) ◽  
pp. 1452-1460
Author(s):  
Osama M Al-Quteimat ◽  
Amer M Amer
Keyword(s):  
Lung Cancer ◽  
Patient Care ◽  
Treatment Option ◽  
Nsclc Patient ◽  
Active Member ◽  
Cost Effective Treatment ◽  
Platinum Based Chemotherapy ◽  
New Treatment ◽  
Egfr Mutant ◽  
Egfr Tkis

Lung cancer is a complex, genetically heterogeneous disease. It is the most common cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents the majority of the diagnosed lung cancer cases. Osimertinib is a new treatment option that demonstrated a superior efficacy over standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) or platinum-based chemotherapy. The safety and efficacy of osimertinib (a third generation EGFR-TKIs) were confirmed by well-designed clinical trials. Consequently, osimertinib was considered a first-line treatment option, particularly in patients with EGFR mutant NSCLC. It has been approved by FDA for the treatment of advance or metastatic NSCLC patients with specific EGFR-mutant NSCLC. As an active member of the multidisciplinary team, pharmacist has a promising role in assuring safe, effective and cost-effective treatment in patient with NSCLC. This review article aims to highlight the latest evidence about osimertinib use as a new treatment option in the clinical practice and to review the potential pharmacist key roles in NSCLC patient care.

scholarly journals Application of immune checkpoint inhibitors in EGFR-mutant non-small-cell lung cancer: from bed to bench

2020 ◽  
Vol 12 ◽  
pp. 175883592093033
Author(s):  
Rui Jin ◽  
Jing Zhao ◽  
Lexin Xia ◽  
Qin Li ◽  
Wen Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Egfr Mutant

Targeted therapies are efficient in the context of oncogenic driver mutations. Epidermal growth factor receptor (EGFR)-mutant lung cancers represent a distinct subset of non-small-cell lung cancer (NSCLC) with marked sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Despite the high response rate to EGFR TKIs in EGFR-mutant lung cancer, resistance and tumor recurrence are unavoidable. Therapeutic options are restricted in patients after exhaustion of targeted therapies. Immune checkpoint inhibitors (ICIs) represent a novel therapeutic option for advanced NSCLC with significant overall survival benefit in registration trials. No superiority in terms of long-term survival was observed in the EGFR mutation subgroup when ICIs were given as monotherapy in second-line treatment in earlier studies. Thus, the appropriate application of ICIs to patients harboring EGFR mutations remains an important field of ongoing research. Here, we discuss different immune checkpoint blockade strategies, including ICIs alone and in combination with TKIs, chemotherapy, radiation, and antiangiogenic agents in EGFR-mutant NSCLC as first-line and subsequent treatments. We also summarize the evidence concerning the heterogeneous molecular features and immune signatures of EGFR mutations and their associations with ICI therapy outcomes. This study was performed to improve our understanding of the optimal mode of immune-based treatment approaches in EGFR-mutant NSCLC.

scholarly journals ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells

2020 ◽  
Author(s):  
Peter Cruz-Gordillo ◽  
Megan E. Honeywell ◽  
Thomas Leete ◽  
Michael J. Lee
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Triple Negative Breast Cancer ◽  
Targeted Therapies ◽  
Triple Negative ◽  
Egfr Signaling ◽  
Oncogene Addiction ◽  
Egfr Inhibition ◽  
Apoptotic Protein ◽  
Egfr Mutant

ABSTRACTTargeted therapies for the treatment of cancer are generally thought to exploit oncogene addiction, a phenomenon in which a single oncogene controls both the growth and survival of the tumor cell. Many well-validated examples of oncogene addiction exist; however, the utility of oncogene targeted therapies varies substantially by cancer context, even among cancers in which the targeted oncogene is similarly dysregulated. For instance, epidermal growth factor receptor (EGFR) signaling can be effectively targeted in EGFR-mutant non-small cell lung cancer (NSCLC), but not in triple-negative breast cancer (TNBC), where EGFR is activated to a similar degree. We find that EGFR controls a similar signaling/transcriptional network in TNBC and EGFR-mutant NSCLC cells, but only NSCLC cells respond to EGFR inhibition by activating cell death. To address this paradox and identify mechanisms that contribute to insensitivity to EGFR inhibition in TNBC, we performed a genome-wide CRISPR-Cas9 genetic knockout screen. Our screen identifies the Elongator (ELP) complex as a mediator of insensitivity to EGFR inhibition in TNBC. Depleting ELP proteins caused high levels of apoptotic cell death, in an EGFR inhibition-dependent manner. We find that the tRNA-modifying function of the ELP complex promotes drug insensitivity, by facilitating expression of the anti-apoptotic protein MCL1. Furthermore, pharmacological inhibition of MCL1 synergizes with EGFR inhibition across a panel of genetically diverse TNBC cells. Taken together, we find that TNBC “addiction” to EGFR signaling is masked by the ELP complex, and our study provides an actionable therapeutic strategy to overcome this resistance mechanism by co-targeting EGFR and MCL1.One sentence summaryThe Elongator Protein (ELP) Complex masks TNBC oncogene “addiction” to EGFR signaling, by promoting expression of the anti-apoptotic protein MCL1.

Managing Resistance to EFGR- and ALK-Targeted Therapies

2017 ◽  
pp. 607-618
Author(s):  
Christine M. Lovly ◽  
Puneeth Iyengar ◽  
Justin F. Gainor
Keyword(s):  
Targeted Therapies ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Mechanisms Of Resistance ◽  
Lung Cancers ◽  
Anaplastic Lymphoma ◽  
Ablative Therapies ◽  
Egfr Mutant

Targeted therapies have transformed the management of non–small cell lung cancer (NSCLC) and placed an increased emphasis on stratifying patients on the basis of genetic alterations in oncogenic drivers. To date, the best characterized molecular targets in NSCLC are the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Despite steady advances in targeted therapies within these molecular subsets, however, acquired resistance to therapy is near universal. Recent preclinical models and translational efforts have provided critical insights into the molecular mechanisms of resistance to EGFR and ALK inhibitors. In this review, we present a framework for understanding resistance to targeted therapies. We also provide overviews of the molecular mechanisms of resistance and strategies to overcome resistance among EGFR-mutant and ALK-rearranged lung cancers. To date, these strategies have centered on the development of novel next-generation inhibitors, rationale combinations, and use of local ablative therapies, such as radiotherapy.

scholarly journals Structure–Activity Relationship (SAR) Study of Spautin-1 to Entail the Discovery of Novel NEK4 Inhibitors

2021 ◽  
Vol 22 (2) ◽  
pp. 635
Author(s):  
Mathias Elsocht ◽  
Philippe Giron ◽  
Laila Maes ◽  
Wim Versées ◽  
Gustavo J. Gutierrez ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Halogen Bond ◽  
Phenyl Group ◽  
Advanced Lung Cancer ◽  
Titration Calorimetry ◽  
Egfr Inhibition ◽  
Egfr Mutant ◽  
Sar Study

Lung cancer is one of the most frequently diagnosed cancers accounting for the highest number of cancer-related deaths in the world. Despite significant progress including targeted therapies and immunotherapy, the treatment of advanced lung cancer remains challenging. Targeted therapies are highly efficacious at prolonging life, but not curative. In prior work we have identified Ubiquitin Specific Protease 13 (USP13) as a potential target to significantly enhance the efficacy of mutant EGFR inhibition. The current study aimed to develop lead molecules for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) by developing potent USP13 inhibitors initially starting from Spautin-1, the only available USP13 inhibitor. A SAR study was performed which revealed that increasing the chain length between the secondary amine and phenyl group and introducing a halogen capable of inducing a halogen bond at position 4’ of the phenyl group, dramatically increased the activity. However, we could not confirm the binding between Spautin-1 (or its analogues) and USP13 using isothermal titration calorimetry (ITC) or thermal shift assay (TSA) but do not exclude binding under physiological conditions. Nevertheless, we found that the anti-proliferative activity displayed by Spautin-1 towards EGFR-mutant NSCLC cells in vitro was at least partially associated with kinase inhibition. In this work, we present N-[2-(substituted-phenyl)ethyl]-6-fluoro-4-quinazolinamines as promising lead compounds for the treatment of NSCLC. These analogues are significantly more effective towards EGFR-mutant NSCLC cells than Spautin-1 and act as potent never in mitosis A related kinase 4 (NEK4) inhibitors (IC50~1 µM) with moderate selectivity over other kinases.

Strategies for Overcoming Acquired Resistance to Epidermal Growth Factor Receptor–Targeted Therapies in Lung Cancer

2012 ◽  
Vol 136 (10) ◽  
pp. 1205-1209 ◽  
Author(s):  
Geoffrey R. Oxnard
Keyword(s):  
Lung Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Targeted Therapies ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Egfr Inhibition ◽  
Epidermal Growth ◽  
Egfr Mutant

Acquired resistance to targeted therapy in epidermal growth factor receptor (EGFR)–mutant lung cancer represents a valuable model for considering strategies of overcoming different types of cellular resistance mechanisms. Using existing data on resistance in EGFR-mutant lung cancer, this review will discuss 3 basic approaches for overcoming resistance to EGFR-targeted therapies: intensification of EGFR inhibition, combination of EGFR inhibitors with other targeted therapies, and changing to anticancer therapies acting via alternate pathways.

scholarly journals Structure-based classification predicts drug response in EGFR-mutant NSCLC

Nature ◽  
2021 ◽  
Vol 597 (7878) ◽  
pp. 732-737
Author(s):  
Jacqulyne P. Robichaux ◽  
Xiuning Le ◽  
R. S. K. Vijayan ◽  
J. Kevin Hicks ◽  
Simon Heeke ◽  
...  
Keyword(s):  
Structure Function ◽  
Targeted Therapies ◽  
Structural Changes ◽  
Drug Sensitivity ◽  
Growth Factor Receptor ◽  
Driver Mutations ◽  
Epidermal Growth ◽  
Function Relationship ◽  
Egfr Mutant ◽  
Relationship Of

AbstractEpidermal growth factor receptor (EGFR) mutations typically occur in exons 18–21 and are established driver mutations in non-small cell lung cancer (NSCLC)1–3. Targeted therapies are approved for patients with ‘classical’ mutations and a small number of other mutations4–6. However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown1,3,7–10. Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure–function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure–function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.

Clinical Utility of Patient-Derived Xenografts to Determine Biomarkers of Prognosis and Map Resistance Pathways in EGFR-Mutant Lung Adenocarcinoma

2015 ◽  
Vol 33 (22) ◽  
pp. 2472-2480 ◽  
Author(s):  
Erin L. Stewart ◽  
Celine Mascaux ◽  
Nhu-An Pham ◽  
Shingo Sakashita ◽  
Jenna Sykes ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Targeted Therapies ◽  
Tumor Biology ◽  
Differentially Expressed Gene ◽  
Mitotic Checkpoint ◽  
Mechanisms Of Resistance ◽  
Cell Lung Carcinoma ◽  
Egfr Mutant ◽  
Egfr Tkis ◽  
Pdx Models

Purpose Although epidermal growth factor receptor (EGFR) –mutated adenocarcinomas initially have high response rates to EGFR tyrosine kinase inhibitors (TKIs), most patients eventually develop resistance. Patient-derived xenografts (PDXs) are considered preferred preclinical models to study the biology of patient tumors. EGFR-mutant PDX models may be valuable tools to study the biology of these tumors and to elucidate mechanisms of resistance to EGFR-targeted therapies. Methods Surgically resected early-stage non–small-cell lung carcinoma (NSCLC) tumors were implanted into nonobese diabetic severe combined immune deficient (NOD-SCID) mice. EGFR TKI treatment was initiated at tumor volumes of 150 μL. Gene expression analysis was performed using a microarray platform. Results Of 33 lung adenocarcinomas with EGFR activating mutations, only 6 (18%) engrafted and could be propagated beyond passage one. Engraftment was associated with upregulation of genes involved in mitotic checkpoint and cell proliferation. A differentially expressed gene set between engrafting and nonengrafting patients could identify patients harboring EGFR-mutant tumor with significantly different prognoses in The Cancer Genome Atlas Lung Adenocarcinoma datasets. The PDXs included models with variable sensitivity to first- and second-generation EGFR TKIs and the monoclonal antibody cetuximab. All EGFR-mutant NSCLC PDXs studied closely recapitulated their corresponding patient tumor phenotype and clinical course, including response pattern to EGFR TKIs. Conclusion PDX models closely recapitulate primary tumor biology and clinical outcome. They may serve as important laboratory models to investigate mechanisms of resistance to targeted therapies, and for preclinical testing of novel treatment strategies.

Induktion von einem nicht-apoptotischen Zelltodes in der humane Zelllinie HepG2 nach Behandlung mit neuen Targeted Therapies

2019 ◽  
Author(s):  
PI Mester ◽  
E Aschenbrenner ◽  
K Pollinger ◽  
C Kunst ◽  
K Gülow ◽  
...  
Keyword(s):  
Targeted Therapies
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