Patient‐derived xenograft models of non‐small cell lung cancer for evaluating targeted drug sensitivity and resistance

Abstract

Patient‐derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non‐small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO‐PrkdcscidHrhr). Histology of SQ, advanced clinical stage (III‐IV), status of lymph node metastasis (N2‐3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18F‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients’ surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next‐generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR‐TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial‐to‐mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR‐TKI resistance.

Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer

“…7c). We established two PDXs from patients with EGFR mutations 19 . PDX LC#7 had EGFR-L858R and a discernible level of AXL, lacking phosphorylated IGF-1R.…”

“…Patient tumor samples were obtained with informed consent. Surgically resected tumor specimens were divided into small pieces (3-5 mm) and implanted into the subcutaneous flank tissue of SHO mice 19 . The PDX LC#7 was from an 81-year-old Japanese male (pT2N2M0, stage IIIA) with lung adenocarcinoma containing EGFR-L858R.…”

“…The PDX LC#7 was from an 81-year-old Japanese male (pT2N2M0, stage IIIA) with lung adenocarcinoma containing EGFR-L858R. The PDX LC#11 was from a 69-year old Japanese male (pT2aN1M1a, stage IV) with lung adenocarcinoma containing the EGFR exon19 deletion 19 . The study protocol was approved by the Ethics Committee on the Use of Laboratory Animals and the Advanced Science Research Center, Kanazawa University, Kanazawa, Japan.…”

Generation of Non-Small Cell Lung Cancer Patient-Derived Xenografts to Study Intratumor Heterogeneity

“…In addition to tumor type, other factors, such as the degree of mouse immunodeficiency (i.e., which immunocompromised strain is used) and size of the grafted specimen could also be important factors. Regarding NSCLC, PDXs have been extensively used in preclinical studies targeting mostly EGFR [ 4 , 7 , 8 ]. Interestingly, published studies have reported a higher grafting efficiency for lung squamous cell carcinomas (LUSC) in comparison to lung adenocarcinomas (LUAD) [ 9 , 10 ].…”

“…A common observation is the high histological resemblance between the primary tumor and early passage mouse xenografts [ 4 , 7 , 9 , 12 , 13 ]. More recent reports have focused on the comparison of the molecular characteristics of primary tumors and the respective mouse counterparts.…”