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L858R emerges as a potential biomarker predicting response of lung cancer models to anti-EGFR antibodies: Comparison of osimertinib vs. cetuximab.

ABSTRACT: EGFR-specific tyrosine kinase inhibitors (TKIs), especially osimertinib, have changed lung cancer therapy, but secondary mutations confer drug resistance. Because other EGFR mutations promote dimerization-independent active conformations but L858R strictly depends on receptor dimerization, we herein evaluate the therapeutic potential of dimerization-inhibitory monoclonal antibodies (mAbs), including cetuximab. This mAb reduces viability of cells expressing L858R-EGFR and blocks the FOXM1-aurora survival pathway, but other mutants show no responses. Unlike TKI-treated patient-derived xenografts, which relapse post osimertinib treatment, cetuximab completely prevents relapses of L858R⁺ tumors. We report that osimertinib's inferiority associates with induction of mutagenic reactive oxygen species, whereas cetuximab's superiority is due to downregulation of adaptive survival pathways (e.g., HER2) and avoidance of mutation-prone mechanisms that engage AXL, RAD18, and the proliferating cell nuclear antigen. These results identify L858R as a predictive biomarker, which may pave the way for relapse-free mAb monotherapy relevant to a large fraction of patients with lung cancer.

SUBMITTER: Marrocco I

PROVIDER: S-EPMC10439256 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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L858R emerges as a potential biomarker predicting response of lung cancer models to anti-EGFR antibodies: Comparison of osimertinib vs. cetuximab.

Marrocco Ilaria I Giri Suvendu S Simoni-Nieves Arturo A Gupta Nitin N Rudnitsky Anna A Haga Yuya Y Romaniello Donatella D Sekar Arunachalam A Zerbib Mirie M Oren Roni R Lindzen Moshit M Fard Damon D Tsutsumi Yasuo Y Lauriola Mattia M Tamagnone Luca L Yarden Yosef Y

Cell reports. Medicine 20230808 8

EGFR-specific tyrosine kinase inhibitors (TKIs), especially osimertinib, have changed lung cancer therapy, but secondary mutations confer drug resistance. Because other EGFR mutations promote dimerization-independent active conformations but L858R strictly depends on receptor dimerization, we herein evaluate the therapeutic potential of dimerization-inhibitory monoclonal antibodies (mAbs), including cetuximab. This mAb reduces viability of cells expressing L858R-EGFR and blocks the FOXM1-aurora ...[more]

PMID: 37557179

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Project description:BackgroundAdvanced non-small cell lung cancer (NSCLC) is often complicated by leptomeningeal metastases (LMs), especially in patients carrying EGFR mutations. EGFR tyrosine kinase inhibitors (TKIs) are the first-line drug for patients with specific gene mutations, such as EGFR exon 19 deletion or exon 21 L858R mutation. However, after long-term TKI use, patients eventually develop drug resistance and acquire new mutations. Acquiring the EGFR T790 M mutation during TKI treatment is a marker for first/second generation TKI resistance. Osimertinib (a third-generation TKI) could overcome this resistance, especially for patients who have already developed NSCLC-LM. Treating NSCLC patients with osimertinib resistance is challenging. Our aim was to investigate whether afatinib is effective in NSCLC-LM patient who showed resistance to osimertinib. Herein, we report two patients with resistance to first- and third-generation TKIs who benefited from second-generation TKI.Case summaryCase one: A 43-year-old man was diagnosed with stage 3A NSCLC with EGFR exon 19 deletion. He underwent surgery and received 4 rounds of chemotherapy (oxaliplatin combined with liposomal paclitaxel), after which the disease was controlled by icotinib (a first-generation TKI) for 4 years. Then, he showed poor drug response and bone metastasis. A liquid biopsy was carried out, and the EGFR L858R/T790 M compound mutation was found. The patient was given osimertinib (a third-generation TKI). The patient was in a stable condition for 2 years and then he developed bilateral peripheral facial palsy. Brain MRI showed enhancement in the left temporal lobe and meninges, and cerebrospinal fluid (CSF) cytology detected tumour cells in the CSF. NSCLC-LM was diagnosed. His performance status (PS) score was 3-4. Liquid biopsy and next-generation sequencing were performed again. Different gene mutations and copy number alterations were found this time, including EGFR L858R, but without the EGFR T790 M mutation. His disease was controlled with intrathecal methotrexate and oral afatinib (a second generation TKI). The patient has shown clinical remission (PS score: 1-2) until now, which is longer than 10 months.Case twoA 50-year-old man was diagnosed with NSCLC in May 2020. He underwent one round of chemotherapy before thoracoscopic partial lobectomy of the right upper lung. Histological study of the lung tissue showed lung adenocarcinoma with the EGFR L858R mutation. Then, the disease was controlled with icotinib. One year later, he was diagnosed with NSCLC-LM. Liquid biopsy and sequencing showed an EGFR L858R/S768I compound mutation. The patient was treated with osimertinib. His condition was stable for 5 months before his central nervous system (CNS) symptoms were exacerbated. Liquid biopsy and sequencing were carried out again, and his gene mutation profile had not changed much. Then, the patient was given afatinib, and his condition has remained stable for 11 months.ConclusionAfatinib might be suitable for NSCLC-LM patients with EGFR compound mutations who show resistance to icotinib and osimertinib, since it might help overcome first- and third-generation TKI resistance.

Project description:MET pathway activation is one of the most common mechanisms of resistance to osimertinib in EGFR-mutant non-small cell lung cancer (NSCLC). We previously demonstrated spatial and temporal heterogeneity in MET pathway activation upon osimertinib resistance in EGFR-mutant NSCLC; however, the functional relevance of these findings is unclear. Here, we generated 19 patient-derived xenografts (PDX) from 9 patients with multi-region and temporal sampling of osimertinib-resistant tumor tissue from patients with EGFR-mutant NSCLC. MET pathway activation was a putative mechanism of osimertinib resistance in 66% (n = 6/9) patients from whom PDXs were generated. Significant spatial and temporal heterogeneity in MET pathway activation was evident. Osimertinib-resistant PDXs with MET amplification by FISH (defined as MET/CEP7 ratio ≥2.0 or mean MET ≥ 6.0 copies/cell) and high-level phospho-MET, but not c-MET expression, had better responses to osimertinib and savolitinib combination than to osimertinib alone. MET polysomy tumors by FISH from both PDXs and patients had evidence of subclonal phospho-MET expression. Select MET polysomy PDX tumors with phospho-MET expression responded better to osimertinib and savolitinib combination than MET polysomy PDX tumors without phospho-MET expression. Our results suggest osimertinib and savolitinib combination is most effective for osimertinib-resistant EGFR-mutant tumors with MET pathway activation as evidenced by phospho-MET. As subclonal MET amplification may be evident in MET polysomy tumor progression, MET polysomy warrants close clinical follow-up with phospho-MET IHC in parallel with FISH diagnostic.SignificanceUsing a novel cohort of in vivo PDX models of MET pathway activation with acquired resistance to osimertinib in EGFR-mutant lung cancer, we demonstrate that phospho-MET may be a clinically relevant assay to guide treatment selection with osimertinib and savolitinib combination. In addition, our work shows that patients with MET polysomy tumors may have subclonal MET amplification and therefore require close follow up for the use of osimertinib and savolitinib combination.

Dataset Information

L858R emerges as a potential biomarker predicting response of lung cancer models to anti-EGFR antibodies: Comparison of osimertinib vs. cetuximab.

Publications

L858R emerges as a potential biomarker predicting response of lung cancer models to anti-EGFR antibodies: Comparison of osimertinib vs. cetuximab.

Similar Datasets

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