Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors

Fassunke, Jana; Müller, Fabienne; Keul, Marina; Michels, Sebastian; Dammert, Marcel A.; Schmitt, Anna; Plenker, Dennis; Lategahn, Jonas; Heydt, Carina; Brägelmann, Johannes; Tumbrink, Hannah L.; Alber, Yannic; Klein, Sebastian; Heimsoeth, Alena; Dahmen, Ilona; Fischer, Rudolf‐Josef; Scheffler, Matthias; Ihle, Michaela A.; Priesner, Vanessa; Scheel, Andreas H.; Wagener, Svenja; Kron, Anna; Frank, Konrad; Garbert, Katia; Persigehl, Thorsten; Püsken, Michael; Haneder, Stefan; Schaaf, Bernhard; Rodermann, Ernst; Engel-Riedel, Walburga; Felip, Enriqueta; Smit, Egbert F.; Merkelbach‐Bruse, Sabine; Reinhardt, Hans Christian; Kast, Stefan M.; Wolf, Jürgen; Rauh, Daniel; Büttner, Reinhard; Sos, Martin L.

doi:10.1038/s41467-018-07078-0

Cited by 114 publications

(111 citation statements)

References 59 publications

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“…39; Supplementary Table S2). Consistent with Fassunke and colleagues (20), our afatinib relative binding-free energies are less affected by G724S versus osimertinib ( Supplementary Table S2). Altogether, these data suggest G724S may function as a resistance mutation to osimertinib in Ex19Del/G724S, but not in L858R/G724S.…”

Section: G724s But Not To L858r/g724ssupporting

confidence: 90%

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On-target Resistance to the Mutant-Selective EGFR Inhibitor Osimertinib Can Develop in an Allele-Specific Manner Dependent on the Original EGFR-Activating Mutation

Brown

Zhang

Westover

et al. 2019

Clinical Cancer Research

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Purpose: The third-generation EGFR inhibitor, osimertinib, is the first mutant-selective inhibitor that has received regulatory approval for the treatment of patients with EGFR-mutant lung cancer. Despite the development of highly selective thirdgeneration inhibitors, acquired resistance remains a significant clinical challenge. Recently, we and others have identified a novel osimertinib resistance mutation, G724S, which was not predicted in in vitro screens. Here, we investigate how G724S confers resistance to osimertinib. Experimental Design: We combine structure-based predictive modeling of G724S in combination with the 2 most common EGFR-activating mutations, exon 19 deletion (Ex19Del) and L858R, with in vitro drug-response models and patient genomic profiling. Results: Our simulations suggest that the G724S mutation selectively reduces osimertinib-binding affinity in the context of Ex19Del. Consistent with our simulations, cell lines transduced with Ex19Del/G724S demonstrate resistance to osimertinib, whereas cells transduced with L858R/ G724S are sensitive to osimertinib. Subsequent clinical genomic profiling data further suggest G724S occurs with Ex19Del but not L858R. Furthermore, we demonstrate that Ex19Del/G724S retains sensitivity to afatinib, but not to erlotinib, suggesting a possible therapy for patients at the time of disease relapse. Conclusions: Altogether, these data suggest that G724S is an allele-specific resistance mutation emerging in the context of Ex19Del but not L858R. Our results fundamentally reframe the problem of targeted therapy resistance from one focused on the "drug-resistance mutation" pair to one focused on the "activating mutation-drug-resistance mutation" trio. This has broad implications across clinical oncology.

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Section: G724s But Not To L858r/g724ssupporting

confidence: 90%

“…Mutation of C797 to serine prevents covalent adduct formation between osimertinib and the EGFR kinase domain (16,17). We (18) and others (14,19,20) have also identified G724S as a mutation that is selected for in osimertinib-resistant tumors.…”

Section: Introductionmentioning

confidence: 56%

On-target Resistance to the Mutant-Selective EGFR Inhibitor Osimertinib Can Develop in an Allele-Specific Manner Dependent on the Original EGFR-Activating Mutation

Brown

Zhang

Westover

et al. 2019

Clinical Cancer Research

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“…[20][21][22][23][24][25] Yet, the effect of oncogene on the tumorigeneses of lung adenocarcinoma and resistance mechanism are still not be fully elucidated. [26][27][28] At the same time, patients and society bear high medical and health costs. Therefore, it is urgent to find effective oncogenes to guide the respiratory doctor to make accurate diagnosis and treatment for different patients.…”

Section: Discussionmentioning

confidence: 99%

<p>Lamin B1 Overexpresses in Lung Adenocarcinoma and Promotes Proliferation in Lung Cancer Cells via AKT Pathway</p>

Li¹,

Li²,

Li³

et al. 2020

OTT

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These authors contributed equally to this workPurpose: This study aims to investigate the biological effect and molecular mechanism of Lamin B1(LMNB1) in lung cancer cells and its significance for the prognosis of lung adenocarcinoma(LUAD) patients. Methods: In this study, Bioinformatics was performed to analyze the expression at mRNA level and prognosis effect of LMNB1 in LUAD from TCGA dataset. The immunohistochemistry(IHC) assay was conducted to analyzed the expression of LMNB1 at the protein level in LUAD tissues. The correlation between the expression of LMNB1 and the clinical factors in patients with LUAD was analyzed. Next, LMNB1 transfected into LUAD cell lines (A549 and PC-9) which was proved by Western blot. CCK8 assay, cloning formation assay, and xenograft assay were conducted to explore the effect and mechanism of LMNB1 on the proliferation of LUAD cell lines in vitro and in vivo. Results:The results of the present study demonstrated that LMNB1 was highly expressed in LUAD tissues and related to tumor stage. High LMNB1 expression was related with more advanced clinicopathological factors such as low degree of differentiation (P=0.02), large tumor size (P<0.01), lymph node metastasis (P<0.01) and higher tumor stage (P<0.01). After knocking down LMNB1, the cell growth rate (P<0.01) and the number of colonies (P<0.01) were significantly reduced, and the level of the proliferating marker Ki67 (P<0.01) was significantly decreased. At the same time, in vivo experiments showed that the tumor volume and tumor of the mice were significantly reduced (P<0.01). Moreover, we found that knockdown LMNB1 can inhibit the proliferation of lung cancer cells by inhibiting AKT phosphorylation by Western blot. Conclusion: In summary, LMNB1 play an of vital roles in the growth of LUAD cells, highlighting its potential as a therapeutic target for the treatment of LUAD patients.

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“…Additional case reports describe other second site mutations such as G724S, G796D, and L792H on osimertinib therapy. The second-generation inhibitor afatinib has been responsive to the acquired G724S mutation (54). E709K and L682V, both activating missense substitutions, were seen after exposure to rociletinib.…”

Section: Mechanisms Of Tki Resistance With Second Site Mutations In Egfrmentioning

confidence: 99%

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer

et al. 2019

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EGFR-activating mutations are observed in approximately 15% to 20% of patients with non-small cell lung cancer. Tyrosine kinase inhibitors have provided an illustrative example of the successes in targeting oncogene addiction in cancer and the role of tumor-specific adaptations conferring therapeutic resistance. The compound osimertinib is a thirdgeneration tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance. The compound has received additional FDA approval as first-line therapy with improvement in progression-free survival by suppressing the activating mutation and preventing the rise of the dominant resistance clone. Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010. However, therapeutic resistance after the administration of third-generation inhibitors is complex and not fully understood, with significant intertumoral and intratumoral heterogeneity. Repeat tissue and plasma analyses on therapy have revealed insights into multiple mechanisms of resistance, including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events. Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance.

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Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors

Cited by 114 publications

References 59 publications

On-target Resistance to the Mutant-Selective EGFR Inhibitor Osimertinib Can Develop in an Allele-Specific Manner Dependent on the Original EGFR-Activating Mutation

On-target Resistance to the Mutant-Selective EGFR Inhibitor Osimertinib Can Develop in an Allele-Specific Manner Dependent on the Original EGFR-Activating Mutation

<p>Lamin B1 Overexpresses in Lung Adenocarcinoma and Promotes Proliferation in Lung Cancer Cells via AKT Pathway</p>

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer

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