Abstract
BackgroundPatient-derived xenograft (PDX) models are important tools in precision medicine and for the development of targeted therapies to treat cancer patients. This study aimed to evaluate our precision medicine strategy that integrates genomic profiling and preclinical drug-screening platforms, in order to personalize cancer treatments using PDX models.MethodsWe performed array-comparative genomic hybridization, microarray, and targeted next-generation sequencing analyses, in order to determine the oncogenic driver mutations. PDX cells were obtained from PDXs and subsequently screened in vitro with 17 targeted agents.ResultsPDX tumors recapitulated the histopathologic and genetic features of the patient tumors. Among the samples from lung cancer patients that were molecularly-profiled, copy number analysis identified unique focal MET amplification in one sample, 033 T, without RTK/RAS/RAF oncogene mutations. Although HER2 amplification in 033 T was not detected in the cancer panel, the selection of HER2-amplified clones was found in PDXs and PDX cells. Additionally, MET and HER2 overexpression were found in patient tumors, PDXs, and PDX cells. Crizotinib or EGFR tyrosine kinase inhibitor treatments significantly inhibited cell growth and impaired tumor sphere formation in 033 T PDX cells.ConclusionsWe established PDX cell models using surgical samples from lung cancer patients, and investigated their preclinical and clinical implications for personalized targeted therapy. Additionally, we suggest that MET and EGFR inhibitor-based therapy can be used to treat MET and HER2-overexpressing lung cancers, without receptor tyrosine kinase /RAS/RAF pathway alterations.
Highlights
Patient-derived xenograft (PDX) models are important tools in precision medicine and for the development of targeted therapies to treat cancer patients
Personalized treatment strategies can be developed based on the oncogenic driver alterations that can be targeted with tyrosine kinase inhibitors (TKIs)
TTF-1 immunohistochemical staining was positive for the tumor cells, and the mass was diagnosed as poorly differentiated metastatic adenocarcinoma (Fig. 1a)
Summary
Patient-derived xenograft (PDX) models are important tools in precision medicine and for the development of targeted therapies to treat cancer patients. This study aimed to evaluate our precision medicine strategy that integrates genomic profiling and preclinical drug-screening platforms, in order to personalize cancer treatments using PDX models. Recent advancements in time and cost reductions of next-generation sequencing technologies, allow for the characterization of the cancer genome in a period when treatment decisions are made, offering the opportunity to increase the therapeutic efficacy by targeting oncogenic driver alterations [1]. Personalized treatment strategies can be developed based on the oncogenic driver alterations that can be targeted with tyrosine kinase inhibitors (TKIs). The oncogenic driver alterations identified in NSCLCs are epidermal growth factor receptor (EGFR), KRAS, BRAF, AKT1, HER2, MEK1, MET, NRAS, PIK3CA mutations or translocations in anaplastic lymphoma kinase (ALK), RET, and ROS1 genes [3].
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