EGFR-A763_Y764insFQEA Is a Unique Exon 20 Insertion Mutation That Displays Sensitivity to Approved and In-Development Lung Cancer EGFR Tyrosine Kinase Inhibitors

Vasconcelos, Pedro; Gergis, Carol; Viray, Hollis; Varkaris, Andreas; Fujii, Masanori; Rangachari, Deepa; VanderLaan, Paul A.; Kobayashi, I; Kobayashi, Susumu; Costa, Daniel B.

doi:10.1016/j.jtocrr.2020.100051

Cited by 45 publications

(51 citation statements)

References 15 publications

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“…Off label use of approved EGFR TKIs is further supported for EGFR exon 18 indels/E709X, exon 19 insertions, exon 20 A763_Y764insFQEA, exon 18 to 25 kinase domain duplications and rearrangements. 1,2,5,9,10 The identification of EGFR TKIs or other therapies with a favorable therapeutic window for patients with EGFR exon 20 insertion-mutated tumors continues to be a significant unmet necessity.…”

Section: Discussionmentioning

confidence: 99%

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Preclinical Characterization of Mobocertinib Highlights the Putative Therapeutic Window of This Novel EGFR Inhibitor to EGFR Exon 20 Insertion Mutations

Vasconcelos

Kobayashi

et al. 2021

JTO Clinical and Research Reports

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Introduction: EGFR exon 20 insertion mutations account for 10% of all EGFR mutations and are mostly insensitive to approved EGFR tyrosine kinase inhibitors (EGFR TKIs). Novel EGFR TKIs have been developed or repurposed for these mutants. A limited number of preclinical studies have detailed these EGFR TKIs. We sought to use commercially available mobocertinib (TAK-788) to characterize the preclinical therapeutic window of this EGFR TKI against EGFR mutations and to probe possible on-target mechanisms of resistance (EGFR-C797S). Methods: We used models of EGFR mutations to probe representative first, second, third generation, and indevelopment EGFR exon 20-active (poziotinib, mobocertinib) TKIs. We also introduced EGFR-C797S to these models to identify mechanisms of resistance. Results: Cells driven by the most common EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N7 71insSVD, H773_V774insH, and others) were inhibited by in-development EGFR TKIs at doses below those affecting EGFR-wildtype; albeit more common EGFR mutations (exon 19 deletions and L858R) were inhibited more readily by mobocertinib and poziotinib. Mobocertinib was able to inhibit the phosphorylation of EGFR in multiple preclinical models. The presence of EGFR-C797S led to greater than 200-fold resistance in proliferation assays probing mobocertinib and osimertinib. A review of clinical studies of mobocertinib disclosed responses that could be lasting. Conclusions: This is one of the initial reports to characterize the novel EGFR TKI mobocertinib and highlights its broad activity against EGFR mutants plus the therapeutic window to EGFR exon 20 insertion mutations; and EGFR-C797S as a possible mechanism of resistance. Further clinical development of mobocertinib merits continuation.

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Section: Discussionmentioning

confidence: 99%

“…Western blot lysates and preparation were performed as previously described. 2,9 Total EGFR, b-actin antibodies (Santa Cruz Biotechnology), and phospho-EGFR (pT1068) antibody (ThermoFisher) were diluted to 1-to-1000, whereas secondary antibodies were diluted to 1-to-10,000.…”

Section: Protein-level Analysismentioning

confidence: 99%

Preclinical Characterization of Mobocertinib Highlights the Putative Therapeutic Window of This Novel EGFR Inhibitor to EGFR Exon 20 Insertion Mutations

Vasconcelos

Kobayashi

et al. 2021

JTO Clinical and Research Reports

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“…Other EGFR-TKIs currently in clinical development-such as poziotinib and CLN-081-have also shown a reproducible therapeutic window in preclinical models [4,5,10]. The clinical trial of poziotinib for EGFR exon 20 insertion mutated NSCLC (ZENITH20, NCT03318939) has led to suboptimal initial efficacy results, with ORR below 15% and median PFS below 5 months (Table1)-results that may be explained by dose limiting skin and gastrointestinal adverse events at the 16 mg/day dosing [11].…”

Section: Discussionmentioning

confidence: 99%

“…Protein-level analysis: Western blot lysates and preparation were performed as previously described [2,10]. Total EGFR, β -actin antibodies (Santa Cruz Biotechnology) and phospho-EGFR (pT1068) antibody (ThermoFisher) were diluted 1:1,000, while secondary antibodies were diluted 1:10,000.…”

Section: Generation Of Compound Egfr-c797s Mutations: the Egfr-c797s mentioning

confidence: 99%

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Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations

Vasconcelos

Kobayashi

et al. 2020

Preprint

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BackgroundEpidermal growth factor receptor (EGFR) exon 20 insertion mutations account for 10% of all EGFR mutations and are mostly insensitive to approved EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Novel EGFR-TKIs have been developed or repurposed for these mutants. A limited number of preclinical studies have detailed these EGFR-TKIs. We sought to use commercially available mobocertinib (TAK-788) to characterize the preclinical therapeutic window of this EGFR-TKI against EGFR mutations and to probe possible on-target mechanisms of resistance (EGFR-C797S).MethodsWe used models of EGFR mutations to probe representative 1st, 2nd, 3rd generation, and in-development EGFR exon 20-active (poziotinib, mobocertinib) TKIs. We also introduced EGFR-C797S to these models to identify mechanisms of resistance.ResultsCells driven by the most common EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, H773_V774insH and others) were inhibited by in-development EGFR TKIs at doses below those affecting EGFR-wildtype; albeit more common EGFR mutations (exon 19 deletions and L858R) were inhibited more readily by mobocertinib and poziotinib. Mobocertinib was able to inhibit phosphorylation of EGFR in multiple preclinical models. The presence of EGFR-C797S led to >200-fold resistance in proliferation assays probing mobocertinib and osimertinib. Review of clinical studies of mobocertinib disclosed responses that could be lasting.ConclusionsThis is one of the initial reports to characterize the novel EGFR TKI mobocertinib and highlights its broad activity against EGFR mutants plus the therapeutic window to EGFR exon 20 insertion mutations; as well as EGFR-C797S as a possible mechanism of resistance. Further clinical development of mobocertinib merits continuation.

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Therapeutic advances in non‐small cell lung cancer: Focus on clinical development of targeted therapy and immunotherapy

Yuan

Zhang

2021

MedComm

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Lung cancer still contributes to nearly one‐quarter cancer‐related deaths in the past decades, despite the rapid development of targeted therapy and immunotherapy in non‐small cell lung cancer (NSCLC). The development and availability of comprehensive genomic profiling make the classification of NSCLC more precise and personalized. Most treatment decisions of advanced‐stage NSCLC have been made based on the genetic features and PD‐L1 expression of patients. For the past 2 years, more than 10 therapeutic strategies have been approved as first‐line treatment for certain subgroups of NSCLC. However, some major challenges remain, including drug resistance and low rate of overall survival. Therefore, we discuss and review the therapeutic strategies of NSCLC, and focus on the development of targeted therapy and immunotherapy in advanced‐stage NSCLC. Based on the latest guidelines, we provide an updated summary on the standard treatment for NSCLC. At last, we discussed several potential therapies for NSCLC. The development of new drugs and combination therapies both provide promising therapeutic effects on NSCLC.

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EGFR-A763_Y764insFQEA Is a Unique Exon 20 Insertion Mutation That Displays Sensitivity to Approved and In-Development Lung Cancer EGFR Tyrosine Kinase Inhibitors

Cited by 45 publications

References 15 publications

Preclinical Characterization of Mobocertinib Highlights the Putative Therapeutic Window of This Novel EGFR Inhibitor to EGFR Exon 20 Insertion Mutations

Preclinical Characterization of Mobocertinib Highlights the Putative Therapeutic Window of This Novel EGFR Inhibitor to EGFR Exon 20 Insertion Mutations

Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations

Therapeutic advances in non‐small cell lung cancer: Focus on clinical development of targeted therapy and immunotherapy

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