B32 Drug Sensitivity and Allele Specificity of First-Line Osimertinib Resistance EGFR Mutations

Starrett, Jacqueline H.; Guernet, Alexis; Cuomo, Maria Emanuela; Poels, Kamrine E.; Rosenburgh, I.K. van Alderwerelt van; Nagelberg, Amy; Farnsworth, Dylan; Price, Kristin S.; Hina, Kazuyoshi; Ashtekar, Kumar Dilip; Gaefele, Mmaserame; Ayeni, Deborah; Stewart, Tyler F.; Kuhlmann, Alexandra; Kaech, Susan M.; Unni, Arun M.; Homer, Robert J.; Lockwood, Will; Michor, Franziska; Goldberg, Sarah B.; Lemmon, Mark A.; Smith, Paul D.; Cross, Darren A.E.; Politi, Katerina

doi:10.1016/j.jtho.2019.12.097

Cited by 2 publications

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“…Liquid biopsy with cerebrospinal fluid (CSF) is a new approach, which has been used successfully in improving the diagnosis and characterization of LM [3] . NSCLC with EGFR sensitive mutation (SM) could acquire resistance to first-line osimertinib through C797S mutation, which might respond to first- or second-generation EGFR inhibitors [4–6] . Herein, we reported a patient with NSCLC acquired resistance to first-line osimertinib.…”

Section: Introductionmentioning

confidence: 99%

“…[3] NSCLC with EGFR sensitive mutation (SM) could acquire resistance to first-line osimertinib through C797S mutation, which might respond to firstor second-generation EGFR inhibitors. [4][5][6] Herein, we reported a patient with NSCLC acquired resistance to first-line osimertinib. LM occurred and EGFR C797S/exon 19 deletion (19del) mutations was detected by next-generation sequencing (NGS) of CSF circulating tumor DNA (ctDNA).…”

Section: Introductionmentioning

confidence: 99%

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Erlotinib combined with bevacizumab and chemotherapy in first line osimertinib-resistant NSCLC patient with leptomeningeal metastasis

Wang

Zhu

et al. 2021

Medicine

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Rationale:Leptomeningeal metastasis (LM) is a fatal complication of advanced non-small cell lung cancer (NSCLC) with a poor prognosis. Osimertinib is a promising option for NSCLC with LM harboring epidermal growth factor receptor (EGFR) mutation. However, therapeutic approaches remain a challenge for osimertinib resistant NSCLCs with LM. Although studies have reported that the first/second-generation EGFR-tyrosine kinase inhibitors were active against osimertinib-resistant NSCLC with EGFR C797S and sensitive mutation (SM), the resistance inevitably occurred due to the development of the EGFR SM/C797S/T790M triple mutations.Patient concerns:A 48-year-old woman was diagnosed with stage IV lung adenocarcinoma harboring the EGFR mutation in the combination of chest computed tomography, biopsy and amplification refractory mutation system-polymerase chain. One year and a half after oral administration of osimertinib, the patient progressed to extensive LM.Diagnoses:Magnetic resonance images of the brain showed extensive LM. Exfoliated tumor cells from cerebrospinal fluid (CSF) were positive detected by lumbar puncture and the cytology examination. EGFR mutations (exon19 E746_T751delinsI and exon20 C797S) in CSF circulating tumor DNA were detected by next-generation sequencing (NGS).Interventions:Pemetrexed (800 mg day 1), cis-platinum (40 mg day 1-3) combined with bevacizumab (400 mg day 1) every 3 weeks were administered to the patient. After 1 cycle, due to optic nerve invasion, erlotinib was applied 150 mg/d combined with previous regimen. The patient continued erlotinib monotherapy after 6 cycles.Outcomes:After LM, erlotinib combined with pemetrexed, cis-platinum and bevacizumab were administered to the patient for 4.25 months based on the CSF NGS. Then, the patient continued erlotinib monotherapy and appeared disease progression after 10 months. The overall survival is 35 months.Lessons:LM is a fatal complication of advanced NSCLC with a poor prognosis. NGS profiling of CSF circulating tumor DNA is important in NSCLC patients with LM and erotinib plus bevacizumab and chemotherapy is a promising option for patients with LM harboring EGFR C797S/SM.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Erlotinib combined with bevacizumab and chemotherapy in first line osimertinib-resistant NSCLC patient with leptomeningeal metastasis

Wang

Zhu

et al. 2021

Medicine

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Genetic determinants ofEGFR-Driven Lung Cancer Growth and Therapeutic ResponseIn Vivo

Foggetti

Cai

et al. 2020

Preprint

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36Cancer genome sequencing has uncovered substantial complexity in the mutational 37 landscape of tumors. Given this complexity, experimental approaches are necessary to 38 establish the impact of combinations of genetic alterations on tumor biology and to uncover 39 genotype-dependent effects on drug sensitivity. In lung adenocarcinoma, EGFR mutations co-40 occur with many putative tumor suppressor gene alterations, however the extent to which 41 these alterations contribute to tumor growth and their response to therapy in vivo has not 42 been explored experimentally. By integrating a novel mouse model of oncogenic EGFR-driven 43Trp53-deficient lung adenocarcinoma with multiplexed CRISPR-Cas9-mediated genome editing 44 and tumor barcode sequencing, we quantified the effects of inactivation of ten putative tumor 45 suppressor genes. Inactivation of Apc, Rb1, or Rbm10 most strongly promoted tumor growth. 46Unexpectedly, inactivation of Lkb1 or Setd2 -which were the strongest drivers of tumor growth 47 in an oncogenic Kras-driven model -reduced EGFR-driven tumors growth. These results were 48 consistent with the relative frequency of these tumor suppressor gene alterations in human 49 EGFR-and KRAS-driven lung adenocarcinomas. Furthermore, Keap1 inactivation reduced the 50 sensitivity of tumors to osimertinib in the EGFR L858R ;p53 flox/flox model. Importantly, in human 51 EGFR/TP53 mutant lung adenocarcinomas, mutations in the KEAP1 pathway correlated with 52 decreased time on tyrosine kinase inhibitor treatment. Our study highlights how genetic 53 alterations can have dramatically different biological consequences depending on the 54 oncogenic context and that the fitness landscape can shift upon drug treatment. 55 56 57 58 During tumor evolution, cancer cells accumulate alterations in oncogenes and tumor 59 suppressor genes, which contribute to many of the hallmarks of cancer 1 . Despite their extensive 60 genomic complexity, tumors are frequently classified based on the presence of a single 61 oncogenic driver mutation, while the function of co-incident tumor suppressor gene alterations 62 is largely ignored. There is emerging evidence that the interplay between oncogenic drivers and 63 tumor suppressor genes may influence tumor fitness and impact treatment response 2 . 64However, the combinatorially vast landscape of genomic alterations makes it difficult, except in 65 the most extreme cases, to glean information about the epistatic interactions between tumor 66 suppressor genes and oncogenes 3 . This complexity makes inferring the relationship between 67 genotype and therapy response even more tenuous. 68Recently, high-throughput, tractable systems that combine autochthonous mouse modeling 69 and genome editing have been developed to directly uncover the functional consequences of 70 genetic alterations during tumorigenesis in vivo 4-10 . However, very few studies have 71 investigated the biological consequences of inactivating tumor suppressor genes in the context 72 of different oncogenic drivers in vivo, a...

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B32 Drug Sensitivity and Allele Specificity of First-Line Osimertinib Resistance EGFR Mutations

Cited by 2 publications

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Erlotinib combined with bevacizumab and chemotherapy in first line osimertinib-resistant NSCLC patient with leptomeningeal metastasis

Erlotinib combined with bevacizumab and chemotherapy in first line osimertinib-resistant NSCLC patient with leptomeningeal metastasis

Genetic determinants ofEGFR-Driven Lung Cancer Growth and Therapeutic ResponseIn Vivo

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