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Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors.

ABSTRACT: UNLABELLED:Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types. SIGNIFICANCE:Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain.

SUBMITTER: Vivanco I

PROVIDER: S-EPMC3354723 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors.

Vivanco Igor I Robins H Ian HI Rohle Daniel D Campos Carl C Grommes Christian C Nghiemphu Phioanh Leia PL Kubek Sara S Oldrini Barbara B Chheda Milan G MG Yannuzzi Nicolas N Tao Hui H Zhu Shaojun S Iwanami Akio A Kuga Daisuke D Dang Julie J Pedraza Alicia A Brennan Cameron W CW Heguy Adriana A Liau Linda M LM Lieberman Frank F Yung W K Alfred WK Gilbert Mark R MR Reardon David A DA Drappatz Jan J Wen Patrick Y PY Lamborn Kathleen R KR Chang Susan M SM Prados Michael D MD Fine Howard A HA Horvath Steve S Wu Nian N Lassman Andrew B AB DeAngelis Lisa M LM Yong William H WH Kuhn John G JG Mischel Paul S PS Mehta Minesh P MP Cloughesy Timothy F TF Mellinghoff Ingo K IK

Cancer discovery 20120331 5

<h4>Unlabelled</h4>Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that targe ...[more]

PMID: 22588883

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Project description:The optimal management of advanced non-small cell lung cancer (NSCLC) with noncanonical epidermal growth factor receptor (EGFR) mutations (i.e., exon 19 deletion and exon 21 L858R) is constrained by the heterogeneous behavior of individual uncommon mutations and limited prospective clinical data in this setting. Despite encouraging results with osimertinib from a recently published phase II trial from South Korea, afatinib remains the only currently approved drug for patients with tumors harboring uncommon EGFR mutations (i.e., S768I, L861Q, and/or G719X). When used at the standard dose of 40 mg daily, afatinib is associated with significant rates of treatment-related adverse events, leading to frequent dose reductions and treatment discontinuations. We report a case of a woman with advanced NSCLC harboring EGFR-G719A mutation treated with afatinib (at an off-label pulse dose strategy that merits further evaluation in prospective studies) with sustained partial response for 20 months with manageable expected toxicities. Subsequent disease progression was mediated by off-target pan-EGFR inhibitor (including osimertinib)-resistant KRAS mutation and not by acquisition of EGFR-T790M. We further present the current state of evidence in the literature behind use of first-, second-, and third-generation tyrosine kinase inhibitors and summarize the evolving spectrum of activity ascribed to osimertinib (and newer EGFR inhibitors with a more favorable therapeutic window and intracranial penetration) in this population of patients with advanced NSCLC and uncommon EGFR mutations. KEY POINTS: Uncommon EGFR mutations characterize a heterogeneous group of patients with advanced non-small cell lung cancer (NSCLC). Afatinib is the only currently U.S. Food and Drug Administration-approved drug for management of advanced NSCLC with uncommon EGFR mutations (S768I, L861Q, and/or G719X). Afatinib treatment at 40 mg daily is associated with high rates of adverse events and dose reductions; alternative strategies including pulse intermittent dosing should be evaluated prospectively. Osimertinib (with favorable safety profile and intracranial penetration) has shown promising results in this population in a phase II trial from South Korea; additional trials are ongoing.

Project description:Background: The EGFR exon 20 insertions (ex20ins) D770_N771insSVD and V769_D770insASV are most frequent in non-small-cell lung cancer (NSCLC) and are associated with intrinsic resistance to currently approved EGFR tyrosine kinase inhibitors (TKIs). A763_Y764insFQEA and D770delinsGY, respectively, account for 3%-8% and 2.0%-4.8% of EGFR ex20ins in NSCLC and are associated with a more favorable response to EGFR-specific TKIs as per case reports. The aim of this study was to elucidate the molecular structures of these mutants and their binding affinities to diverse EGFR TKIs and compare the clinical outcomes in NSCLC patients harboring these mutations. Methods: A real-world cohort study was conducted to evaluate and compare the clinical outcomes of EGFR TKIs among NSCLC patients with different EGFR ex20ins mutants in response to EGFR TKIs. The structures of A763_Y764insFQEA and D770delinsGY were also analyzed and drug binding simulations were performed. Results: With a median follow-up of 24.0 months, the first-line objective response rate (ORR), disease control rate (DCR), and median progression-free survival (PFS) were, respectively, 0 (0/16), 50.0% (8/16), and 2.07 months (95%CI, 0-6.25) in patients harboring D770_N771insSVD and V769_D770insASV variants and 33.3% (4/12), 83.3% (10/12), and 9.97 months (95%CI, 4.75-15.19) in patients with A763_Y764insFQEA and D770delinsGY variants. There was a significant difference between the PFS of these two subgroups (median, 9.97 vs.2.07 months, HR = 0.33, 95%CI, 0.13-0.85, p = 0.02). Similarly, the PFS was significantly longer after second-line treatment with EGFR TKIs in patients harboring A763_Y764insFQEA and D770delinsGY compared to those with other insertions (median, 6.77 vs.2.23 months, HR = 0.14, p < 0.001). Computational simulations indicated that A763_Y764insFQEA and D770delinsGY mutants were structurally similar to wild-type EGFR. In contrast, the C-helix and phosphate-binding loop of D770_N771insSVD and V769_D770insASV had shifted into the drug-binding pocket, resulting in significant steric hindrance and a lack of affinity for the currently approved EGFR inhibitors. Conclusion: NSCLC patients harboring A763_Y764insFQEA and D770delinsGY insertions of EGFR are responsive to the currently approved EGFR TKIs as opposed to patients with the D770_N771insSVD and V769_D770insASV variants. Therefore, A763_Y764insFQEA and D770delinsGY should be classified as active mutations among heterogeneous EGFR ex20ins subtypes and the carriers can be treated with the suitable EGFR TKIs.

Dataset Information

Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors.

Publications

Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors.

Similar Datasets

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