Covalent EGFR Inhibitors: Binding Mechanisms, Synthetic Approaches, and Clinical Profiles

Hossam, Monia; Lasheen, Deena S.; Abouzid, Khaled A. M.

doi:10.1002/ardp.201600063

Cited by 33 publications

(25 citation statements)

References 88 publications

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“…The action mode of targeted agents is generally predicted through complex computer assisted modeling, followed by biological validation and molecular imaging [24][25][26] . However, intracellular drug interaction may also affect drug efficacy.…”

Section: Discussionmentioning

confidence: 99%

TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration confer resistance to MEK inhibition in pancreatic cancer

Zhao

Dierichs

et al. 2020

Cell Death Discov.

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Oncogenic KRAS mutations are encountered in more than 90% of pancreatic ductal adenocarcinomas. MEK inhibition has failed to procure any clinical benefits in mutant RAS-driven cancers including pancreatic ductal adenocarcinoma (PDAC). To identify potential resistance mechanisms underlying MEK inhibitor (MEKi) resistance in PDAC, we investigated lysosomal drug accumulation in PDAC models both in vitro and in vivo. Mouse PDAC models and human PDAC cell lines as well as human PDAC xenografts treated with the MEK inhibitor trametinib or refametinib led to an enhanced expression of lysosomal markers and enrichment of lysosomal gene sets. A time-dependent, increase in lysosomal content was observed upon MEK inhibition. Strikingly, there was a strong activation of lysosomal biogenesis in cell lines of the classical compared to the basal-like molecular subtype. Increase in lysosomal content was associated with nuclear translocation of the Transcription Factor EB (TFEB) and upregulation of TFEB target genes. siRNA-mediated depletion of TFEB led to a decreased lysosomal biogenesis upon MEK inhibition and potentiated sensitivity. Using LC-MS, we show accumulation of MEKi in the lysosomes of treated cells. Therefore, MEK inhibition triggers lysosomal biogenesis and subsequent drug sequestration. Combined targeting of MEK and lysosomal function may improve sensitivity to MEK inhibition in PDAC.

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Section: Discussionmentioning

confidence: 99%

TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration confer resistance to MEK inhibition in pancreatic cancer

Zhao

Dierichs

et al. 2020

Cell Death Discov.

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“…Although we could not calculate the accurate incidence of vortex keratopathy following the use of EGFR inhibitors as chemotherapy due to the nature of this study, the condition does not seem uncommon when dealing with recently developed agents. Vandetanib is a second-generation EGFR inhibitor and osimertinib is a third-generation EGFR inhibitor that can target T790 M and EGFR TKI-sensitizing mutations while sparing wildtype EGFR [18]. ABT-414 is an investigational compound.…”

Section: Discussionmentioning

confidence: 99%

Markedly increased ocular side effect causing severe vision deterioration after chemotherapy using new or investigational epidermal or fibroblast growth factor receptor inhibitors

et al. 2020

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Background: We sought to describe corneal epithelial changes after using epidermal (EGFR) or fibroblast growth factor receptor (FGFR) inhibitors as chemotherapy and to clarify incidence and prognosis. Materials: Retrospective chart review. Results: Among 6871 patients and 17 EGFR or FGFR inhibitors, 1161 patients (16.9%) referred for ophthalmologic examination. In total, 1145 patients had disease-related or unrelated ocular complications. Among 16 patients with treatment-related ocular complications, three patients had treatment-related radiation retinopathy and one patient showed treatment-related corneal ulcer. Finally the authors identified that, in 12 patients, three EGFR inhibitors and two FGFR inhibitors caused corneal epithelial lesions. Vandetanib, Osimertinib, and ABT-414 caused vortex keratopathy in nine patients, while ASP-5878 and FPA-144 caused epithelial changes resembling corneal dysmaturation in three patients. The mean interval until symptoms appeared was 246 days with vandetanib, 196 days with osimertinib, 30 days with ABT-414, 55 days with ASP-5878, and 70 days with FPA-144. The mean of the lowest logarithm of minimal angle of resolution visual acuity results of the right and left eyes after chemotherapy were 0.338 and 0.413. The incidence rates of epithelial changes were 15.79% with vandetanib, 0.5% with osimertinib, 100% with ABT-414, 50.0% with ASP-5878, and 18.2% with FPA-144. After excluding deceased patients and those who were lost to follow-up or still undergoing treatment, we confirmed the reversibility of corneal lesions after the discontinuation of each agent. Seven patients showed full recovery of their vision and corneal epithelium, while three achieved a partial level of recovery. Although patients diagnosed with glioblastoma used prophylactic topical steroids before and during ABT-414 therapy, all developed vortex keratopathy. Conclusions: EGFR and FGFR inhibitors are chemotherapy agents that could make corneal epithelial changes. Contrary to the low probability of ocular complication with old EGFR drugs, recently introduced EGFR and FGFR agents showed a high incidence of ocular complication with severe vision distortion. Doctors should forewarn patients planning chemotherapy with these agents that decreased visual acuity could develop due to corneal epithelial changes and also reassure them that the condition could be improved after the end of treatment without the use of steroid eye drops.

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“…To overcome acquired resistance caused by T790M, second-generation EGFR-TKIs such as afatinib and dacomitinib have been developed (Table 1) [9,26]. These agents have shown more potent inhibition of TK activity through covalent and irreversible binding to the cysteine at codon 797 (C797) in the TK domain (Fig.…”

Section: Development Of Egfr-tkismentioning

confidence: 99%

“…Osimertinib is a third-generation EGFR-TKI that selectively inhibits mutated-EGFR through irreversible and covalent binding to C797 in the TK domain ( Fig. 4 and Table 1) [9, 26,32,33]. In a phase 3 trial comparing osimertinib with chemotherapy for patients who developed acquired resistance caused by T790M after first-line EGFR-TKI treatment (AURA3 trial), osimertinib showed a superior PFS over chemotherapy (10.1 months versus 4.4 months; hazard ratio [HR], 0.30; P < 0.001) [34].…”

mentioning

confidence: 99%

Treatment of Non-small Cell Lung Cancer with <i>EGFR</i>-mutations

Yoneda

Imanishi

Ichiki

et al. 2019

J UOEH

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The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene and development of tyrosine kinase inhibitors (TKIs) of EGFR have achieved a paradigm shift in treatment strategy of non-small cell lung cancer (NSCLC). For advanced NSCLC harboring activating EGFR mutations, an EGFR-TKI is preferably prescribed as it provides a superior survival benefit over platinum-based chemotherapy. To further improve the therapeutic outcomes, more potent EGFR-TKIs through irreversible inhibition of tyrosine kinase have been developed. In a recent clinical trial, an irreversible EGFR-TKI (osimertinib) showed a superior survival benefit with lower toxicity profile. In addition, combination treatments such as an EGFR-TKI plus platinum-based chemotherapy may achieve a long-term survival. For earlier-stage resectable NSCLC with EGFR-mutations, several clinical trials to assess the efficacy of EGFR-TKIs in pre-operative induction setting and in postoperative adjuvant setting are now ongoing. Here we review and discuss the current status and future perspectives of treatment for EGFR-mutated NSCLC.

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Covalent EGFR Inhibitors: Binding Mechanisms, Synthetic Approaches, and Clinical Profiles

Cited by 33 publications

References 88 publications

TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration confer resistance to MEK inhibition in pancreatic cancer

TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration confer resistance to MEK inhibition in pancreatic cancer

Markedly increased ocular side effect causing severe vision deterioration after chemotherapy using new or investigational epidermal or fibroblast growth factor receptor inhibitors

Treatment of Non-small Cell Lung Cancer with <i>EGFR</i>-mutations

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