The Impact of On-Target Resistance Mediated by EGFR-T790M or EGFR-C797S on EGFR Exon 20 Insertion Mutation Active Tyrosine Kinase Inhibitors
Introduction: Mechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors have not been extensively studied in either robust preclinical models or patient-derived rebiopsy specimens. We sought to characterize on-target resistance mutations identified in EGFR exon 20 insertion-mutat...
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Elsevier
2024-01-01
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| Series: | JTO Clinical and Research Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666364323001571 |
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| author | Ikei S. Kobayashi, MD, PhD William Shaffer, MS Hollis Viray, MD Deepa Rangachari, MD Paul A. VanderLaan, MD, PhD Susumu S. Kobayashi, MD, PhD Daniel B. Costa, MD, PhD |
| author_facet | Ikei S. Kobayashi, MD, PhD William Shaffer, MS Hollis Viray, MD Deepa Rangachari, MD Paul A. VanderLaan, MD, PhD Susumu S. Kobayashi, MD, PhD Daniel B. Costa, MD, PhD |
| author_sort | Ikei S. Kobayashi, MD, PhD |
| collection | DOAJ |
| description | Introduction: Mechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors have not been extensively studied in either robust preclinical models or patient-derived rebiopsy specimens. We sought to characterize on-target resistance mutations identified in EGFR exon 20 insertion-mutated lung cancers treated with mobocertinib or poziotinib and evaluate whether these mutations would or would not have cross-resistance to next-generation inhibitors zipalertinib, furmonertinib, and sunvozertinib. Methods: We identified mechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors and then used preclinical models of EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, V773_C774insH) plus common EGFR mutants to probe inhibitors in the absence/presence of EGFR-T790M or EGFR-C797S. Results: Mobocertinib had a favorable therapeutic window in relation to EGFR wild type for EGFR exon 20 insertion mutants, but the addition of EGFR-T790M or EGFR-C797S negated the observed window. Zipalertinib had a favorable therapeutic window for cells driven by EGFR-A767_V769dupASV or EGFR-D770_N771insSVD in the presence or absence of EGFR-T790M. Furmonertinib and sunvozertinib had the most favorable therapeutic windows in the presence or absence of EGFR-T790M in all cells tested. EGFR-C797S in cis to all EGFR mutations evaluated generated dependent cells that were resistant to the covalent EGFR tyrosine kinase inhibitors mobocertinib, zipalertinib, furmonertinib, sunvozertinib, poziotinib, and osimertinib. Conclusions: This report highlights that poziotinib and mobocertinib are susceptible to on-target resistance mediated by EGFR-T790M or -C797S in the background of the most prevalent EGFR exon 20 insertion mutations. Furmonertinib, sunvozertinib, and to a less extent zipalertinib can overcome EGFR-T790M compound mutants, whereas EGFR-C797S leads to covalent inhibitor cross-resistance—robust data that support the limitations of mobocertinib and should further spawn the development of next-generation covalent and reversible EGFR exon 20 insertion mutation active inhibitors with favorable therapeutic windows that are less vulnerable to on-target resistance. |
| first_indexed | 2024-03-08T10:28:44Z |
| format | Article |
| id | doaj.art-9d6f86ae7ca94cdea9028f4d32112c40 |
| institution | Directory Open Access Journal |
| issn | 2666-3643 |
| language | English |
| last_indexed | 2024-03-08T10:28:44Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
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| series | JTO Clinical and Research Reports |
| spelling | doaj.art-9d6f86ae7ca94cdea9028f4d32112c402024-01-27T06:58:22ZengElsevierJTO Clinical and Research Reports2666-36432024-01-0151100614The Impact of On-Target Resistance Mediated by EGFR-T790M or EGFR-C797S on EGFR Exon 20 Insertion Mutation Active Tyrosine Kinase InhibitorsIkei S. Kobayashi, MD, PhD0William Shaffer, MS1Hollis Viray, MD2Deepa Rangachari, MD3Paul A. VanderLaan, MD, PhD4Susumu S. Kobayashi, MD, PhD5Daniel B. Costa, MD, PhD6Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MassachusettsDivision of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MassachusettsDivision of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MassachusettsDivision of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MassachusettsDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, MassachusettsDivision of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, JapanDivision of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Corresponding author. Address for correspondence: Daniel B. Costa, MD, PhD, Division of Medical Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215.Introduction: Mechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors have not been extensively studied in either robust preclinical models or patient-derived rebiopsy specimens. We sought to characterize on-target resistance mutations identified in EGFR exon 20 insertion-mutated lung cancers treated with mobocertinib or poziotinib and evaluate whether these mutations would or would not have cross-resistance to next-generation inhibitors zipalertinib, furmonertinib, and sunvozertinib. Methods: We identified mechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors and then used preclinical models of EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, V773_C774insH) plus common EGFR mutants to probe inhibitors in the absence/presence of EGFR-T790M or EGFR-C797S. Results: Mobocertinib had a favorable therapeutic window in relation to EGFR wild type for EGFR exon 20 insertion mutants, but the addition of EGFR-T790M or EGFR-C797S negated the observed window. Zipalertinib had a favorable therapeutic window for cells driven by EGFR-A767_V769dupASV or EGFR-D770_N771insSVD in the presence or absence of EGFR-T790M. Furmonertinib and sunvozertinib had the most favorable therapeutic windows in the presence or absence of EGFR-T790M in all cells tested. EGFR-C797S in cis to all EGFR mutations evaluated generated dependent cells that were resistant to the covalent EGFR tyrosine kinase inhibitors mobocertinib, zipalertinib, furmonertinib, sunvozertinib, poziotinib, and osimertinib. Conclusions: This report highlights that poziotinib and mobocertinib are susceptible to on-target resistance mediated by EGFR-T790M or -C797S in the background of the most prevalent EGFR exon 20 insertion mutations. Furmonertinib, sunvozertinib, and to a less extent zipalertinib can overcome EGFR-T790M compound mutants, whereas EGFR-C797S leads to covalent inhibitor cross-resistance—robust data that support the limitations of mobocertinib and should further spawn the development of next-generation covalent and reversible EGFR exon 20 insertion mutation active inhibitors with favorable therapeutic windows that are less vulnerable to on-target resistance.http://www.sciencedirect.com/science/article/pii/S2666364323001571EGFR-T790MEGFR-C797SMobocertinibZipalertinibFurmonertinibSunvozertinib |
| spellingShingle | Ikei S. Kobayashi, MD, PhD William Shaffer, MS Hollis Viray, MD Deepa Rangachari, MD Paul A. VanderLaan, MD, PhD Susumu S. Kobayashi, MD, PhD Daniel B. Costa, MD, PhD The Impact of On-Target Resistance Mediated by EGFR-T790M or EGFR-C797S on EGFR Exon 20 Insertion Mutation Active Tyrosine Kinase Inhibitors JTO Clinical and Research Reports EGFR-T790M EGFR-C797S Mobocertinib Zipalertinib Furmonertinib Sunvozertinib |
| title | The Impact of On-Target Resistance Mediated by EGFR-T790M or EGFR-C797S on EGFR Exon 20 Insertion Mutation Active Tyrosine Kinase Inhibitors |
| title_full | The Impact of On-Target Resistance Mediated by EGFR-T790M or EGFR-C797S on EGFR Exon 20 Insertion Mutation Active Tyrosine Kinase Inhibitors |
| title_fullStr | The Impact of On-Target Resistance Mediated by EGFR-T790M or EGFR-C797S on EGFR Exon 20 Insertion Mutation Active Tyrosine Kinase Inhibitors |
| title_full_unstemmed | The Impact of On-Target Resistance Mediated by EGFR-T790M or EGFR-C797S on EGFR Exon 20 Insertion Mutation Active Tyrosine Kinase Inhibitors |
| title_short | The Impact of On-Target Resistance Mediated by EGFR-T790M or EGFR-C797S on EGFR Exon 20 Insertion Mutation Active Tyrosine Kinase Inhibitors |
| title_sort | impact of on target resistance mediated by egfr t790m or egfr c797s on egfr exon 20 insertion mutation active tyrosine kinase inhibitors |
| topic | EGFR-T790M EGFR-C797S Mobocertinib Zipalertinib Furmonertinib Sunvozertinib |
| url | http://www.sciencedirect.com/science/article/pii/S2666364323001571 |
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