The EGFR C797S Mutation Confers Resistance to a Novel EGFR Inhibitor CLN-081 to EGFR Exon 20 Insertion Mutations

Kagawa, Yosuke; Hayashida, Takuma; Liu, Jie; Mori, Shunta; Izumi, Hiroki; Kumagai, Shogo; Udagawa, Hibiki; Hattori, Noboru; Goto, Kōichi; Kobayashi, Susumu

doi:10.1016/j.jtocrr.2023.100462

Cited by 4 publications

(5 citation statements)

References 32 publications

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“…Currently, identified resistance mechanisms in clinical samples include PIK3CA E545K, MAP2K2 S94L, MET amplification, EGFR amplification, and CDK6 amplification. In drugs such as Poziotinib, Mobocertinib, Zipalertinib, and Osimertinib, the emergence of the C797S mutation may promote clinical resistance by covalently binding to the EGFR ATP-binding site ( 88 ). In this regard, the use of Hsp90 inhibitors alone or in combination with other therapies may yield unexpected therapeutic effects ( 106 ).…”

Section: Discussionmentioning

confidence: 99%

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The current landscape, advancements, and prospects in the treatment of patients with EGFR exon 20 insertion mutations warrant scientific elucidation

Man,

Sun,

Chen

et al. 2024

Front. Oncol.

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Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most prevalent mutation in non-small cell lung cancer (NSCLC), following the 19del and L858R mutations. The unique nature of the EGFR ex20ins mutation poses challenges for the effectiveness of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). As a result, chemotherapy remains the primary and more effective treatment approach. However, with advancements in time and technology, numerous experimental studies have revealed the potential of novel drugs and therapies to have stronger inhibitory effects on EGFR ex20ins mutations. In this comprehensive review, we provide an overview of the current treatment landscape, recent advancements, and the prospects for patients with advanced NSCLC characterized by EGFR ex20ins mutations.

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Section: Discussionmentioning

confidence: 99%

“…However, over time, some patients inevitably develop resistance to Zipalertinib. Kagawa et al demonstrated that similar to Poziotinib, all Zipalertinib-resistant clones harbored the EGFR C797S mutation (88). Ba/F3 cells carrying C797S (Ba/F3-C797S) exhibited resistance to EGFR tyrosine kinase inhibitors.…”

Section: Zipalertinib (Cln-081 Tas6417)mentioning

confidence: 99%

The current landscape, advancements, and prospects in the treatment of patients with EGFR exon 20 insertion mutations warrant scientific elucidation

Man,

Sun,

Chen

et al. 2024

Front. Oncol.

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“…Occupation of the pocket under the P-loop by introducing hydrophobic groups could be a positive medicinal chemistry strategy to address this issue (e.g., Mobocertinib and LDC0496). Third, on-target drug-resistance mutations have already been found in cell lines treated with poziotinib and CLN-081, namely T790 M and C797S mutations. , While the T790 M mutation might be circumvented by covalent pyrimidine inhibitors, as observed for osimertinib in the context of the EGFR L858R/T790 M and 19del/T790 M double mutants, the C797S mutation is yet to be addressed clinically through the design of fourth-generation EGFR inhibitors. Therefore, all EGFR Ex20ins mutation inhibitors reported to date are likely to be ineffective against C797S-resistant mutations.…”

Section: Discussionmentioning

confidence: 99%

Structural Mechanism and Inhibitors Targeting EGFR Exon 20 Insertion (Ex20ins) Mutations

Chen,

Hu,

Patterson

et al. 2023

J. Med. Chem.

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Epidermal growth factor receptor (EGFR) targeted therapy is one of the most important and effective strategies to combat EGFR mutant nonsmall-cell lung cancer (NSCLC). However, a substantial number of patients bearing EGFR exon 20 insertion (Ex20ins) mutations respond poorly to common EGFR targeted therapies. This clinical need remained unmet until recently, when the EGFR Ex20ins mutation inhibitor mobocertinib was approved by the FDA. Despite this progress, the structural mechanisms of EGFR Ex20ins mutation resistance and characterization of inhibitor binding modes have not been systematically summarized. Herein, we analyze the structural mechanisms for ligand binding and resistance and summarize recent developments for the reported inhibitors of EGFR Ex20ins mutations. Furthermore, this Perspective aims to provide insights for the design of the next generation of EGFR Ex20ins inhibitors.

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“…It is likely that both on-target and off-target aberrations similar to those seen with other EGFR -mutated NSCLCs will be identified with time. Our group and others have described in preclinical models that EGFR -C797S is a pan-resistance mutation when occurring in compound with typical EGFR exon 20 insertions in cell lines treated with mobocertinib, poziotinib, and zipalertinib ( 58 , 125 ). EGFR -T790M in compound with exon 20 insertions appears to render resistance to mobocertinib and poziotinib ( 58 , 109 , 126 ).…”

Section: Preclinical Models Of Egfr and Erbb2-directed Therapies In N...mentioning

confidence: 99%

EGFR exon 20 insertion mutations and ERBB2 mutations in lung cancer: a narrative review on approved targeted therapies from oral kinase inhibitors to antibody-drug conjugates

Sentana‐Lledo¹,

Academia²,

Viray³

et al. 2023

Transl Lung Cancer Res

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Background and Objective This review will provide an overview of EGFR and ERBB2 mutations in non-small-cell lung cancer (NSCLC) with a focus on recent clinical approvals. Methods We obtained data from the literature in accordance with narrative review reporting guidelines. Key Content and Findings EGFR mutations are present in up to 15–20% of all NSCLCs; amongst these, 10% correspond to kinase domain insertions in exon 20. Structurally similar, ERBB2 ( HER2 ) mutations occurs in 1–4% of NSCLCs, mostly consisting of insertions or point mutations. The majority of EGFR exon 20 insertions occur within the loop following the regulatory C-helix and activate the kinase domain of EGFR without generating a therapeutic window to gefitinib, erlotinib, afatinib, dacomitinib or osimertinib. Mobocertinib represents a novel class of covalent EGFR inhibitors with a modest therapeutic window to these mutants and induces anti-tumor responses in a portion of patients [at 160 mg/day: response rate of <30% with duration of response (DoR) >17 months and progression-free survival (PFS) of >7 months] albeit with mucocutaneous and gastrointestinal toxicities. The bi-specific EGFR-MET antibody amivantamab-vmjw has modest but broad preclinical activity in EGFR-driven cancers and specifically for EGFR exon 20 insertion-mutated NSCLC has response rates <40% and PFS of <8.5 months at the cost of both infusion-related plus on-target toxicities. Both drugs were approved in 2021. The clinical development of kinase inhibitors for ERBB2 -mutated NSCLC has been thwarted by mucocutaneous/gastrointestinal toxicities that preclude a pathway for drug approval, as the case of poziotinib. However, the activation of ERBB2 has allowed for repurposing of antibody-drug conjugates (ADCs) that target ERBB2 with cytotoxic payloads. The FDA approved fam-trastuzumab deruxtecan-nxki in 2022 for NSCLC based on response rate of >55%, DoR >9 months, PFS >8 months and manageable adverse events (including cytopenias, nausea and less commonly pneumonitis). Other therapies in clinical development include sunvozertinib and zipalertinib, among others. In addition, traditional cytotoxic chemotherapy has some activity in these tumors. Conclusions The approvals of mobocertinib, amivantamab, and trastuzumab deruxtecan represent the first examples of precision oncology for EGFR exon 20 insertion-mutated and ERBB2 -mutated NSCLCs.

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The EGFR C797S Mutation Confers Resistance to a Novel EGFR Inhibitor CLN-081 to EGFR Exon 20 Insertion Mutations

Cited by 4 publications

References 32 publications

The current landscape, advancements, and prospects in the treatment of patients with EGFR exon 20 insertion mutations warrant scientific elucidation

The current landscape, advancements, and prospects in the treatment of patients with EGFR exon 20 insertion mutations warrant scientific elucidation

Structural Mechanism and Inhibitors Targeting EGFR Exon 20 Insertion (Ex20ins) Mutations

EGFR exon 20 insertion mutations and ERBB2 mutations in lung cancer: a narrative review on approved targeted therapies from oral kinase inhibitors to antibody-drug conjugates

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