EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios
<i>Epidermal growth factor receptor</i> (<i>EGFR</i>) exon 20 insertion mutations account for a tenth of all <i>EGFR</i> mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that can respond to multipl...
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MDPI AG
2021-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/12/3561 |
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| author | Ikei S. Kobayashi Hollis Viray Deepa Rangachari Susumu S. Kobayashi Daniel B. Costa |
| author_facet | Ikei S. Kobayashi Hollis Viray Deepa Rangachari Susumu S. Kobayashi Daniel B. Costa |
| author_sort | Ikei S. Kobayashi |
| collection | DOAJ |
| description | <i>Epidermal growth factor receptor</i> (<i>EGFR</i>) exon 20 insertion mutations account for a tenth of all <i>EGFR</i> mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that can respond to multiple classes of approved EGFR-TKIs. We sought to characterize variants involving <i>EGFR</i>-D770 to <i>EGFR</i>-G770 position equivalence changes that structurally allow for response to irreversible 2nd generation EGFR-TKIs. Our group used preclinical models of EGFR exon 20 insertion mutations to probe representative 1st (erlotinib), 2nd (afatinib, dacomitinib), 3rd generation (osimertinib) and EGFR exon 20 insertion mutant-active (poziotinib, mobocertinib) TKIs; we also queried the available clinical literature plus our institutional database to enumerate clinical outcomes. <i>EGFR</i>-D770>GY and other <i>EGFR</i> insertions with a G770 equivalence were identified at a frequency of 3.96% in separate cohorts of <i>EGFR</i> exon 20 insertion mutated lung cancer (<i>n</i> = 429). Cells driven by EGFR-D770>GY were insensitive to erlotinib and osimertinib, displayed sensitivity to poziotinib and mobocertinib and were uniquely sensitive to afatinib and dacomitinib in comparison with other more typical EGFR exon 20 insertion mutations using proliferation and biochemical assays. Clinical cases with <i>EGFR</i>-G770 equivalence from the literature and our center mirrored the preclinical data, with radiographic responses and clinical benefits restricted to afatinib, dacomitinib, poziotinib and mobocertinib, but not to erlotinib or osimertinib. Although they are rare, at <4% of all exon 20 insertion mutations, EGFR-G770 equivalence exon 20 insertion mutations are sensitive to approved 2nd generation EGFR TKIs and EGFR exon 20 insertion mutant-active TKIs (mobocertinib and poziotinib). EGFR-D770>GY and other insertions with a G770 equivalence join EGFR-A763_Y764insFQEA as exon 20 insertion mutationsresponsive to approved EGFR TKIs beyond mobocertinib; this data should be considered for clinical care, genomic profiling reports and clinical trial elaboration. |
| first_indexed | 2024-03-10T04:25:17Z |
| format | Article |
| id | doaj.art-e65dd9a2c7cf4e4f9bca2f5cb2dd4e8f |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T04:25:17Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-e65dd9a2c7cf4e4f9bca2f5cb2dd4e8f2023-11-23T07:39:29ZengMDPI AGCells2073-44092021-12-011012356110.3390/cells10123561EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical ScenariosIkei S. Kobayashi0Hollis Viray1Deepa Rangachari2Susumu S. Kobayashi3Daniel B. Costa4Department of Medicine, Division of Medical Oncology, Harvard Medical School, Boston, MA 02215, USADepartment of Medicine, Division of Medical Oncology, Harvard Medical School, Boston, MA 02215, USADepartment of Medicine, Division of Medical Oncology, Harvard Medical School, Boston, MA 02215, USADepartment of Medicine, Division of Medical Oncology, Harvard Medical School, Boston, MA 02215, USADepartment of Medicine, Division of Medical Oncology, Harvard Medical School, Boston, MA 02215, USA<i>Epidermal growth factor receptor</i> (<i>EGFR</i>) exon 20 insertion mutations account for a tenth of all <i>EGFR</i> mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that can respond to multiple classes of approved EGFR-TKIs. We sought to characterize variants involving <i>EGFR</i>-D770 to <i>EGFR</i>-G770 position equivalence changes that structurally allow for response to irreversible 2nd generation EGFR-TKIs. Our group used preclinical models of EGFR exon 20 insertion mutations to probe representative 1st (erlotinib), 2nd (afatinib, dacomitinib), 3rd generation (osimertinib) and EGFR exon 20 insertion mutant-active (poziotinib, mobocertinib) TKIs; we also queried the available clinical literature plus our institutional database to enumerate clinical outcomes. <i>EGFR</i>-D770>GY and other <i>EGFR</i> insertions with a G770 equivalence were identified at a frequency of 3.96% in separate cohorts of <i>EGFR</i> exon 20 insertion mutated lung cancer (<i>n</i> = 429). Cells driven by EGFR-D770>GY were insensitive to erlotinib and osimertinib, displayed sensitivity to poziotinib and mobocertinib and were uniquely sensitive to afatinib and dacomitinib in comparison with other more typical EGFR exon 20 insertion mutations using proliferation and biochemical assays. Clinical cases with <i>EGFR</i>-G770 equivalence from the literature and our center mirrored the preclinical data, with radiographic responses and clinical benefits restricted to afatinib, dacomitinib, poziotinib and mobocertinib, but not to erlotinib or osimertinib. Although they are rare, at <4% of all exon 20 insertion mutations, EGFR-G770 equivalence exon 20 insertion mutations are sensitive to approved 2nd generation EGFR TKIs and EGFR exon 20 insertion mutant-active TKIs (mobocertinib and poziotinib). EGFR-D770>GY and other insertions with a G770 equivalence join EGFR-A763_Y764insFQEA as exon 20 insertion mutationsresponsive to approved EGFR TKIs beyond mobocertinib; this data should be considered for clinical care, genomic profiling reports and clinical trial elaboration.https://www.mdpi.com/2073-4409/10/12/3561lung cancerEGFR exon 20 insertionD770>GYafatinibdacomitinibpoziotinib |
| spellingShingle | Ikei S. Kobayashi Hollis Viray Deepa Rangachari Susumu S. Kobayashi Daniel B. Costa EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios Cells lung cancer EGFR exon 20 insertion D770>GY afatinib dacomitinib poziotinib |
| title | EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios |
| title_full | EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios |
| title_fullStr | EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios |
| title_full_unstemmed | EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios |
| title_short | EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios |
| title_sort | egfr d770 gy and other rare egfr exon 20 insertion mutations with a g770 equivalence are sensitive to dacomitinib or afatinib and responsive to egfr exon 20 insertion mutant active inhibitors in preclinical models and clinical scenarios |
| topic | lung cancer EGFR exon 20 insertion D770>GY afatinib dacomitinib poziotinib |
| url | https://www.mdpi.com/2073-4409/10/12/3561 |
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