Antitumor activity of HM781‐36B, a highly effective pan‐HER inhibitor in erlotinib‐resistant NSCLC and other EGFR‐dependent cancer models

Young, Mi; Lee, Kwang-Ok; Kim, Mi-Ra; Song, Ji Yeon; Lee, Kyu Hang; Park, Jong-Min; Chae, Y.; Kim, Young Hoon; Suh, Kwee Hyun; Lee, Gwan Sun; Park, Seung Bum; Kim, Maeng Sup

doi:10.1002/ijc.26276

Cited by 69 publications

(50 citation statements)

References 41 publications

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“…Previous studies of EGFR exon 20 insertions suggested that the drug-binding pocket of exon 20 may be altered, affecting drug binding 17 . In a study by Cha et al 29 , the authors demonstrate that poziotinib (HM781-36B) covalently binds and inhibits mutant EGFR and HER2 kinases and induces cell death in EGFR and HER2 mutated NSCLC cell lines in vitro. Poziotinib, like afatinib, also contains a small terminal group and a flexible quinazoline core.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

Robichaux

Elamin

Tan

et al. 2018

Nat Med

374

403

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Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.

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Section: Resultsmentioning

confidence: 99%

Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

Robichaux

Elamin

Tan

et al. 2018

Nat Med

374

403

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“…It also impaired cell survival in several human NSCLC cell lines, and in each of them, afatinib was more potent than the reversible inhibitors erlotinib, gefitinib and lapatinib or the irreversible inhibitor canertinib. Many subsequent studies have confirmed the growth-inhibiting and cytotoxic properties of afatinib in a wide range of NSCLC cell lines (Cha et al 2012; Chang and Wang 2012; Greulich et al 2012; Kim et al 2012a, b; Köhler et al 2012; Lee et al 2013; Nanjo et al 2012; Ninomiya et al 2013; Pfeifer et al 2010; Rho et al 2011; Solca et al 2012; Takezawa et al 2010; Wang et al 2012). The greater potency of afatinib compared to erlotinib, gefitinib, canertinib or lapatinib was also confirmed in later studies (Ninomiya et al 2013; Solca et al 2012; Takezawa et al 2010).…”

Section: Effects At the Cellular Levelmentioning

confidence: 90%

“…For EGFR, this was directly confirmed by experiments demonstrating that kinase activity remained inhibited for several hours following afatinib treatment of cell lines for a short time and subsequent washout (Solca et al 2012). The irreversibility of afatinib effects was independently confirmed for both EGFR and HER2 based on autophosphorylation experiments (Cha et al 2012). …”

Section: Effects At the Cellular Levelmentioning

confidence: 92%

“…The potency of afatinib on the L858R/T790M double mutation of EGFR, known to be resistant to erlotinib, gefitinib and lapatinib, was reduced but still in the nanomolar range (Table 1) (Cha et al 2012; Solca et al 2012; Sos et al 2010). When tested in a panel of 52 other tyrosine and serine/threonine kinases, afatinib only inhibited the kinase activity of ErbB family members (Li et al 2008).…”

Section: Effects At the Molecular Levelmentioning

confidence: 99%

“…The greater potency of afatinib compared to erlotinib, gefitinib, canertinib or lapatinib was also confirmed in later studies (Ninomiya et al 2013; Solca et al 2012; Takezawa et al 2010). The cytotoxic effects of afatinib were selective for cancer cells with ErbB dysregulation (EC 50 1.2–60 nM) as compared to non-malignant cell lines such as Hs-27 human and Balb/c3T3 mouse fibroblasts (EC 50 2,835 and 2,105 nM, respectively) (Cha et al 2012). Of note, not all NSCLC cell lines are equally sensitive to growth inhibition by afatinib.…”

Section: Effects At the Cellular Levelmentioning

confidence: 99%

See 2 more Smart Citations

A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer

Modjtahedi

Cho

Michel

et al. 2014

Naunyn-Schmiedeberg's Arch Pharmacol

102

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Afatinib (also known as BIBW 2992) has recently been approved in several countries for the treatment of a distinct type of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. Such covalent binding irreversibly inhibits the tyrosine kinase activity of these receptors, resulting in reduced auto-and transphosphorylation within the ErbB dimers and inhibition of important steps in the signal transduction of all ErbB receptor family members. Afatinib inhibits cellular growth and induces apoptosis in a wide range of cells representative for non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer and several other cancer types exhibiting abnormalities of the ErbB network. This translates into tumour shrinkage in a variety of in vivo rodent models of such cancers. Afatinib retains inhibitory effects on signal transduction and in vitro and in vivo cancer cell growth in tumours resistant to reversible EGFR inhibitors, such as those exhibiting the T790M mutations. Several combination treatments have been explored to prevent and/or overcome development of resistance to afatinib, the most promising being those with EGFR-or HER2-targeted antibodies, other tyrosine kinase inhibitors or inhibitors of downstream signalling molecules.

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

Hossam

Lasheen

Abouzid

2016

Archiv der Pharmazie

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Being overexpressed in several types of cancer, the epidermal growth factor receptor (EGFR) is considered one of the key therapeutic targets in oncology. Although many first-generation EGFR inhibitors had been FDA approved for the treatment of certain types of cancer, patients soon developed resistance to these reversible ATP competitive inhibitors via mutations in the kinase domain of EGFR. A new trend was adopted to design covalent irreversible inhibitors, that is, second- and third-generation inhibitors. Second-generation inhibitors can inhibit the mutant forms but, unfortunately, they had dose limiting side effects due to wild-type EGFR inhibition. Third-generation inhibitors emerged shortly, which were capable of inhibiting the mutant forms exclusively while sparing the wild type. Many other strategies have also been developed to reduce the risk of covalent interactions with off-targets, thus improving the pharmacokinetic and/or pharmacodynamic profile of the antiproliferative agents. In this review, we focused mainly on second- and third-generation EGFR inhibitors, their binding mechanisms (either docking studies or co-crystallized structures), their synthetic approaches, clinical profiles, and limitations.

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Antitumor activity of HM781‐36B, a highly effective pan‐HER inhibitor in erlotinib‐resistant NSCLC and other EGFR‐dependent cancer models

Cited by 69 publications

References 41 publications

Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer

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

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