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case_images: Diagnosis of EGFR V786M mutation and first-line therapy. (A) CT scan of lung window captured on April 16, 2020. Elevated SUV of bone lesion (B) and lung nodule (C) in PET-CT scan.(D) Next-generation sequencing (NGS) panel results showed an epidermal growth factor receptor (EGFR) mutation V786M in exon 20. (E) CT scan of the lung window captured on July 20, 2020, post first-line therapy. Significant abnormal findings noted (arrow).
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case_images: A 69-year-old never-smoker woman in good clinical conditions was referred to a local hospital due to a solid lesion in the left lung on April 2020 (Figure 1A). A immunohistochemistry positivity. A brain MRI revealed no abnormalities Positron emission tomography (PET) CT scan indicated elevated standardized uptake value (SUV) of bone lesion (Figure 1B) and lung nodule (Figure 1C). Next-generation sequencing (NGS) of tumor tissue revealed a variant (GUG > AUG) in the exon 20 of EGFR, resulting in amino acid substitution V786M (Val786Met) (Figure 1D). A first-line therapy of pemetrexed and carboplatin combined with anti-programmed death-1 (PD-1) antibody tislelizumab was used for 6 cycles, with best response of stable of disease (Figure 1E). In April 2021, progressive disease was defined due to the appearance of intracranial metastases (Supplementary Figures S1A, B). The primary lung cancer remained stable (Supplementary Figure S1C). A second-line therapy of 4 cycles of nab-paclitaxel plus vascular endothelial growth factor receptor (VEGFR) TKI anlotinib was used, with best response of stable disease (Supplementary Figures S1D-F). Anlotinib was used for another 4 months for maintenance therapy (Supplementary Figures S1G-I).
case_images: Responses of EGFR TKIs as third- and fourth-line therapy. Chest scanning CT before and after EGFR TKI treatment: (A, B) Brain MRI before gefitinib on November 10, 2021. (C, D) Brain MRI after gefitinib on December 8, 2021. (E, F) Brain MRI after almonertinib on February 9, 2022. (G, H) Chest CT scan before gefitinib on November 10, 2021. (I, J) Chest CT scan after almonertinib on February 9, 2022. (K, L) Chest CT and brain MRI 4 months post-almonertinib on April 14, 2022. Significant abnormal findings noted (arrow).
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case_images: Brain MRI detected multiple intracranial metastases (Figures 2A, B). A repeated MRI scan showing multiple brain lesions on December 8, 2021, suggested that new metastases were observed after 1 month of gefitinib (Figures 2C, D). A brain MRI and chest CT scan (Figures 2E, F) and an indicated shrinkage of intracranial metastases and primary lung cancer (Figures 2G-J) were assessed as a partial response. A follow-up radiological examination of chest CT and brain MRI on April 14, 2022, confirmed the response as partial response (Figures 2K, L).
case_images: Timeline of patient history. TTD, time to discontinuation; PFS, progress-free survival; Pem, pemetrexed; CBP, carboplatin.
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case_images: The treatment timeline of this patient is illustrated in Figure 3.
case_images: EGFR V786M mutation may facilitate the dimerization of EGFR, while it does not affect the binding of TKI. (A) Structure of the EGFR TK domain in the asymmetry dimer (PDB: 4LL0). The activator kinase is colored in slate, the receiver kinase in wheat. The predicted 3D structure of the V786M mutation is shown in cartoon (green) with V786 indicated in a red box. The modeled complex structure of the EGFR : EGFR homodimer, in which the N-lobe of the first EGFR (receiver) binds to the C-lobe of the second EGFR (activator) in a head-to-tail manner. (B) A close-up view of the dimer interface. M786 (blue) may strength the interaction between the EGFR dimer by protruding into the activator kinase domain (slate surface). (C) Structural alignment between EGFR V786M (green) and the wild-type protein (grey) with AMPPNP (red) bound (PDB: 3VJO). V786M induces conformational change in the N lobe region. (D) Analysis of EGFR mutations (PDB: 5ZWJ, 5GNK, 5GTY, 4ZAU, 4I22, 3UG2, 5Y9T, 6LUD). V786M locates in a different position from previously reported EGFR mutations which affects the binding of TKI (cyan) such as G719S, T790M, C797S, and L858R (highlighted in red). TK domain; tyrosine kinase domain. TKI, tyrosine kinase inhibitor; WT, wild-type.
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case_images: V786M mutation, we predicted the 3D structure of EGFR V768M mutation using publicly available tools (Figure 4A). V786 is located in the N-terminus of the receptor at the dimerization interface. Structural analysis indicated that V786M protrudes into the kinase dimer interface and may increase the dimer interaction due to the larger size of methionine (Figure 4B). Intriguingly, the active state of EGFR is achieved through a "head-to-tail" configuration in asymmetric dimers and V786M could stabilize the interaction to keep the kinase domain for autophosphorylation and downstream signaling (Figures 4C, D).