Osimertinib Resistance: Molecular Mechanisms and Emerging Treatment Options

Cancers, Journal Year: 2023, Volume and Issue: 15(3), P. 841 - 841

Published: Jan. 30, 2023

The development of tyrosine kinase inhibitors (TKIs) targeting the mutant epidermal growth factor receptor (EGFR) protein initiated success story targeted therapies in non-small-cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, is currently indicated as first-line therapy patients with NSCLC sensitizing EGFR mutations, second-line who present resistance-associated mutation T790M after treatment previous EGFR-TKIs, and adjuvant for early stage resected NSCLC, harboring mutations. Despite durable responses advanced resistance to osimertinib, similar other therapies, inevitably develops. Understanding mechanisms resistance, including both EGFR-dependent -independent molecular pathways, well their therapeutic potential, represents an unmet need thoracic oncology. Interestingly, differential develop when osimertinib administered versus setting, indicating importance selection pressure clonal evolution tumor cells. Standard approaches progression include targetable genetic alteration detected, cytotoxic chemotherapy or without antiangiogenic immunotherapeutic agents. Deciphering how use agents EGFR-positive current challenge clinical research. Emerging options involve combinations different novel EGFR-TKI inhibitors. Research should also be focused on standardization liquid biopsies order facilitate monitoring alterations osimertinib.

Language: Английский

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Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR–Mutant, Metastatic Nonsquamous Non–Small Cell Lung Cancer

Journal of Clinical Oncology, Journal Year: 2024, Volume and Issue: 42(34), P. 4029 - 4039

Published: Aug. 22, 2024

PURPOSE Epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for -mutant, metastatic non–small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum–based chemotherapy with or without pembrolizumab TKI-resistant, nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837 ). METHODS Adults pathologically confirmed stage IV NSCLC, documented DEL19 L858R mutation, progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles 200 mg placebo once every 3 weeks plus four carboplatin cisplatin then maintenance pemetrexed. Dual primary end points progression-free survival (PFS) overall (OS). Final PFS testing was completed at second interim analysis (IA2; data cutoff, December 3, 2021); OS tested final (FA; January 17, 2023). Efficacy boundaries one-sided P = .0117 OS. RESULTS Four hundred ninety-two (n 245) 247). At IA2, median 5.6 months versus 5.5 (hazard ratio [HR], 0.80 [95% CI, 0.65 0.97]; .0122). FA, 15.9 14.7 months, respectively (HR, 0.84 0.69 1.02]; .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% recipients 38.6% recipients. CONCLUSION Addition did not significantly prolong KEYNOTE-789.

Language: Английский

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Ivonescimab Plus Chemotherapy in Non–Small Cell Lung Cancer With EGFR Variant

JAMA, Journal Year: 2024, Volume and Issue: 332(7), P. 561 - 561

Published: May 31, 2024

Importance For patients with non–small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited. Objective To compare the efficacy of ivonescimab plus chemotherapy alone for relapsed advanced or metastatic epidermal growth factor receptor ( ) variant. Design, Setting, and Participants Double-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total 322 eligible were enrolled. Interventions received (n = 161) placebo pemetrexed carboplatin once every weeks 4 cycles, followed by maintenance therapy pemetrexed. Main Outcomes Measures The primary end point was progression-free survival intention-to-treat population assessed an independent radiographic review committee (IRRC) per Response Evaluation Criteria Solid Tumors version 1.1. results first planned interim analysis are reported. Results Among groups, median age 59.6 vs 59.4 years 52.2% 50.9% female. As March 10, 2023, follow-up time 7.89 months. Median 7.1 (95% CI, 5.9-8.7) months group 4.8 4.2-5.6) (difference, 2.3 months; hazard ratio [HR], 0.46 [95% 0.34-0.62]; P < .001). prespecified subgroup showed benefit favoring over across almost all subgroups, including EGFR-TKI (HR, 0.48 CI 0.35-0.66]) those brain metastases 0.40 0.22-0.73]). objective response rate 50.6% 42.6%-58.6%) 35.4% 28.0%-43.3%) 15.6% 5.3%-26.0%]; .006). overall data not mature; cutoff, 69 (21.4%) had died. Grade higher treatment-emergent adverse events occurred 99 (61.5%) 79 (49.1%) group, most common which chemotherapy-related. immune-related 10 (6.2%) (2.5%) group. vascular endothelial factor–related 5 (3.1%) Conclusions Ivonescimab significantly improved tolerable safety profile TKI-treated cancer. Trial Registration ClinicalTrials.gov Identifier: NCT05184712

Language: Английский

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Therapeutic advances of targeting receptor tyrosine kinases in cancer

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 14, 2024

Abstract Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression certain RTKs, are critical creating environments conducive tumor development. Following discovery, extensive research has revealed how RTK dysregulation contributes oncogenesis, with many subtypes showing dependency on aberrant signaling for proliferation, survival progression. These findings paved the way targeted therapies that aim inhibit crucial biological pathways cancer. As result, RTKs emerged as primary targets anticancer therapeutic Over past two decades, this led synthesis validation numerous small molecule kinase inhibitors (TKIs), now effectively utilized treating various types. In manuscript we provide comprehensive understanding context We explored alterations specific receptors across different malignancies, special dedicated examination current inhibitors, highlighting potential therapies. By integrating latest evidence, seek elucidate pivotal biology efficacy inhibition promising treatment outcomes.

Language: Английский

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PIK3CA mutation as an acquired resistance driver to EGFR-TKIs in non-small cell lung cancer: Clinical challenges and opportunities

Pharmacological Research, Journal Year: 2024, Volume and Issue: 202, P. 107123 - 107123

Published: March 2, 2024

Epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have significantly enhanced the treatment outcomes in non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, occurrence of acquired resistance to EGFR-TKIs is an unavoidable outcome observed these patients. Disruption PI3K/AKT/mTOR signaling pathway can contribute emergence TKIs cancer. The PIK3CA mutations following with lead against EGFR-TKIs. This review provides overview current perspectives regarding involvement development Furthermore, we outline state-of-the-art therapeutic strategies targeting We highlight role mutation as mechanism EGFR-mutant NSCLC. Crucially, explore PIK3CA-mediated cancer, aiming optimize effectiveness treatment.

Language: Английский

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Structure-based Virtual Screening, Molecular Docking, Molecular Dynamics Simulation, and Metabolic Reactivity Studies of Quinazoline Derivatives for their Anti-EGFR Activity Against Tumor Angiogenesis

Current Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 31(5), P. 595 - 619

Published: March 9, 2023

Epidermal growth factor receptor (EGFR/HER-1) and its role in tumor development progression through the mechanism of angiogenesis is prevalent non-small lung cancer, head neck cholangiocarcinoma & glioblastoma. Previous treatments targeting oncogenic activity EGFR's kinase domain have been hindered by acquired mutational resistance side effects from existing drugs like erlotinib, highlighting need for new EGFR inhibitors structure- based drug designing.The research aims to develop novel quinazoline derivatives structure-based virtual screening, molecular docking, dynamics simulation potentially interact with impede angiogenic phenomenon.Quinazoline were retrieved filtered PubChem database using screening Lipinski rule five drug-likeness studies. Molecular docking-based methods then carried out identify top leads.A total 1000 retrieved, 671 compounds possessing druglike properties after applying filters. Further filtration ADME toxicity filters yielded 28 good pharmacokinetic profiles. Docking-based identified seven better binding scores than control drug, dacomitinib. After cross-checking scores, three QU524, QU571, QU297 selected study 100 ns interval Desmond module Schrodinger maestro understand their conformational stability.The results showed that leads exhibited affinity stability erlotinib. These also had pharmacodynamic profiles did not violate Lipinski's limits. The findings suggest these potential target inhibit EGFR-associated phenomenon angiogenesis.

Language: Английский

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Treatment strategies and drug resistance mechanisms in adenocarcinoma of different organs

Drug Resistance Updates, Journal Year: 2023, Volume and Issue: 71, P. 101002 - 101002

Published: Aug. 22, 2023

Adenocarcinoma is a common type of malignant tumor, originating from glandular epithelial cells in various organs, such as pancreas, breast, lung, stomach, colon, rectus, and prostate. For patients who lose the opportunity for radical surgery, medication available to provide potential clinical benefits. However, drug resistance big obstacle obtain desired prognosis. In this review, we summary treatment strategies mechanisms adenocarcinoma different including pancreatic cancer, gastric adenocarcinoma, colorectal lung prostate cancer. Although underlying molecular involved vary one organ other, there are several targets that universal targeting these molecules could potentially reverse adenocarcinomas.

Language: Английский

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Targeting oncogenic kinases: Insights on FDA approved tyrosine kinase inhibitors

European Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 970, P. 176484 - 176484

Published: March 11, 2024

Language: Английский

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Targeting PI3K/AKT/mTOR Signaling to Overcome Drug Resistance in Cancer

Chemico-Biological Interactions, Journal Year: 2024, Volume and Issue: 396, P. 111055 - 111055

Published: May 17, 2024

Language: Английский

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Targeting HER3 to overcome EGFR TKI resistance in NSCLC

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 4, 2024

Receptor tyrosine kinases (RTKs) play a crucial role in cellular signaling and oncogenic progression. Epidermal growth factor receptor kinase inhibitors (EGFR TKIs) have become the standard treatment for advanced non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations, but resistance frequently emerges between 10 to 14 months. A significant this is of human EGFR 3 (HER3), an family member. Despite its significance, effective targeting HER3 still developing. This review aims bridge gap by deeply examining HER3’s pivotal contribution TKI spotlighting emerging HER3-centered therapeutic avenues, including monoclonal antibodies (mAbs), TKIs, antibody-drug conjugates (ADCs). Preliminary results indicate combining HER3-specific treatments TKIs enhances antitumor effects, leading increased objective response rate (ORR) prolonged overall survival (OS) resistant cases. Embracing HER3-targeting therapies represents transformative approach against emphasizes importance further research optimize patient stratification understand mechanisms.

Language: Английский

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