CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation

Kashima, Kenji; Kawauchi, Hiroki; Tanimura, Hiromi; Tachibana, Yukako; Chiba, Takashi; Torizawa, Takuya; Sakamoto, Hiroshi

doi:10.1158/1535-7163.mct-20-0229

Cited by 110 publications

(113 citation statements)

References 49 publications

(48 reference statements)

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“…To validate our simulation results and identify detailed structural differences between the apo EGFR L858R/T790M and EGFR L858R/T790M –osimertinib systems, we compared the representative structures of these two systems with the crystal structure extracted from Protein Data Bank ( Figure 5 ), respectively. For the unavailability of EGFR L858R/T790M –osimertinib structures, we selected EGFR L858R/T790M/C797S –osimertinib (PDB ID: 6LUD) as a reference, which was reported to show similar conformational effects with only lower affinity regarding EGFR L858R/T790M [ 58 ]. The crystal structure of EGFR L858R/T790M/C797S –osimertinib adopted an active conformation as we discussed above, with an extended A loop and a closely interacting ion pair K745-E762.…”

Section: Resultsmentioning

confidence: 99%

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

et al. 2021

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Dual-targeting therapeutics by coadministration of allosteric and orthosteric drugs is drawing increased attention as a revolutionary strategy for overcoming the drug-resistance problems. It was further observed that the occupation of orthosteric sites by therapeutics agents has the potential to enhance allosteric ligand binding, which leads to improved potency of allosteric drugs. Epidermal growth factor receptor (EGFR), as one of the most critical anti-cancer targets belonging to the receptor tyrosine kinase family, represents a quintessential example. It was revealed that osimertinib, an ATP-competitive covalent EGFR inhibitor, remarkably enhanced the affinity of a recently developed allosteric inhibitor JBJ-04-125-02 for EGFRL858R/T790M. Here, we utilized extensive large-scale molecular dynamics simulations and the reversed allosteric communication to untangle the detailed molecular underpinning, in which occupation of osimertinib at the orthosteric site altered the overall conformational ensemble of EGFR mutant and reshaped the allosteric site via long-distance signaling. A unique intermediate state resembling the active conformation was identified, which was further stabilized by osimertinib loading. Based on the allosteric communication pathway, we predicted a novel allosteric site positioned around K867, E868, H893, and K960 within the intermediate state. Its correlation with the orthosteric site was validated by both structural and energetic analysis, and its low sequence conservation indicated the potential for selective targeting across the human kinome. Together, these findings not only provided a mechanistic basis for future clinical application of the dual-targeting therapeutics, but also explored an innovative perception of allosteric inhibition of tyrosine kinase signaling.

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Section: Resultsmentioning

confidence: 99%

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

et al. 2021

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“…Although most patients with LUAD harboring EGFR-TKI-sensitizing mutations have an initial responsiveness to EGFR-TRKI treatment, LUAD cells will inevitably develop acquired EGFR-TKI resistance under drug selective pressure. Secondary mutations, including EGFR-T790M mutations and other mutations within the EGFR domain, mutations in MAPK, PI3K and cell cycle genes and amplifications of other oncogenes lead to acquired drug resistance of LUAD cells to EGFR-TKI (50,51). In addition, 20-30% of LUAD patients with EGFR sensitive mutations are insensitive to EGFR-TKI and display intrinsic drug resistance (14).…”

Section: Discussionmentioning

confidence: 99%

Targeting histone deacetylase enhances the therapeutic effect of Erastin-induced ferroptosis in EGFR-activating mutant lung adenocarcinoma

Zhang¹,

Sun²,

Zhong³

et al. 2021

Transl Lung Cancer Res

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Background: Intrinsic or acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is common, thus strategies for the management of EGFR-TKIs resistance are urgently required. Ferroptosis is a recently discovered form of cell death that has been implicated in tumorigenesis and resistance treatment. Accumulating evidence suggests that ferroptosis can be therapeutically exploited for the treatment of solid tumors; however, whether ferroptosis can be targeted to treat EGFR mutant lung cancer and/or overcome the resistance to EGFR-TKIs is still unknown. Methods:The effect of ferroptosis inducers on a panel of EGFR mutant lung cancer cell lines, including those with EGFR-TKI intrinsic and acquired (generated by long-term exposure to the third-generation EGFR-TKI osimertinib), was determined using cytotoxicity assays. Further, drug candidates to enhance the effect of ferroptosis inducers were screened through implementing WGCNA (weighted gene co-expression network analysis) and CMAP (connectivity map) analysis. Flow cytometry-based apoptosis and lipid hydroperoxides measurement were used to evaluate the cell fates after treatment.Results: Compared with EGFR-TKI-sensitive cells, those with intrinsic or acquired resistance to EGFR-TKI display high sensitivity to ferroptosis inducers. In addition, Vorinostat, a clinically used inhibitor targeting histone deacetylase, can robustly enhance the efficacy of ferroptosis inducers, leading to a dramatic increase of hydroperoxides in EGFR mutant lung cancer cells with intrinsic or acquired resistance to EGFR-TKI. Mechanistically, Vorinostat promotes ferroptosis via xCT downregulation.Conclusions: Ferroptosis-inducing therapy shows promise in EGFR-activating mutant lung cancer cells that display intrinsic or acquired resistance to EGFR-TKI. Histone deacetylase inhibitor (HDACi)Vorinostat can further promote ferroptosis by inhibiting xCT expression.

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“…In the present study, postoperative third‐generation EGFR‐TKIs significantly reduced risk of disease recurrence when compared to first‐generation EGFR‐TKIs, providing a preferred option in the adjuvant setting. Furthermore, EGFR C797S mutation is one of the main mechanisms of resistance to osimertinib; to address this issue, the fourth‐generation EGFR inhibitor CH7233163 was developed 41 …”

Section: Discussionmentioning

confidence: 99%

The role of EGFR‐TKIs as adjuvant therapy in EGFR mutation‐positive early‐stage NSCLC: A meta‐analysis

Lin

Chu

et al. 2021

Thoracic Cancer

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Background The role of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) is not clear in early‐stage nonsmall‐cell lung cancer (NSCLC) patients. This meta‐analysis aims to compare the efficacy and safety of EGFR‐TKIs as adjuvant therapy with chemotherapy or placebo in NSCLC patients harboring EGFR mutations. Patients and Methods Pubmed, Embase, and Cochrane databases were searched for randomized controlled trials. The hazard ratio (HR) of disease‐free survival (DFS) and overall survival (OS) as well as the risk ratio (RR) of severe adverse events were merged. Results Seven articles from five studies from 1843 records, a total of 1227 patients, were included in the analysis. The HR for DFS was 0.38 (95% confidence interval [CI] 0.22–0.63), in favor of EGFR‐TKIs. However, no significant benefit of OS was seen (HR = 0.61, 95% CI 0.31–1.22). Treatment benefit was more pronounced in patients with advanced disease stage and longer duration of medication, EGFR exon 19 deletion mutation, and treatment with third‐generation EGFR‐TKIs. Adjuvant targeted therapy may cause few adverse events compared with chemotherapy (RR = 0.28, 95% CI 0.09–0.94). The possibility of severe adverse events for the first‐generation drugs was significantly lower than for third‐generation drugs. Conclusion In EGFR mutation‐positive patients with stage IB–IIIA NSCLC, compared with adjuvant chemotherapy or placebo, adjuvant EGFR‐TKIs should effectively improve the patient's DFS, but not effectively improve OS. Disease stage, treatment duration, mutation types, and therapeutic drugs could affect the degree of benefit. Adjuvant EGFR‐TKIs had more favorable tolerability than chemotherapy, especially with the usage of first‐generation drugs.

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CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation

Cited by 110 publications

References 49 publications

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

Targeting histone deacetylase enhances the therapeutic effect of Erastin-induced ferroptosis in EGFR-activating mutant lung adenocarcinoma

The role of EGFR‐TKIs as adjuvant therapy in EGFR mutation‐positive early‐stage NSCLC: A meta‐analysis

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