Use of Ex Vivo Patient-Derived Tumor Organotypic Spheroids to Identify Combination Therapies for HER2 Mutant Non-Small Cell Lung Cancer

• Published in: Clinical cancer research Vol. 26; no. 10; pp. 2393 - 2403
• Main Authors: Ivanova, Elena, Kuraguchi, Mari, Xu, Man, Portell, Andrew J, Taus, Luke, Diala, Irmina, Lalani, Alshad S, Choi, Jihyun, Chambers, Emily S, Li, Shuai, Liu, Shengwu, Chen, Ting, Barbie, Thanh U, Oxnard, Geoffrey R, Haworth, Jacob J, Wong, Kwok-Kin, Dahlberg, Suzanne E, Aref, Amir A, Barbie, David A, Bahcall, Magda, Paweletz, Cloud P, Jänne, Pasi A
• Format: Journal Article
• Language: English
• Published: United States 15-05-2020
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Proliferation - drug effects; Female; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Quinolines - administration & dosage; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Spheroids, Cellular; Trastuzumab - administration & dosage; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-19-1844

Evaluating drug responses using primary patient-derived cells
represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib combinations in
mutant non-small cell lung cancer (NSCLC) patient
enograft-
erived
rganotypic
pheroids (XDOTS) using a short-term
system.
We generated two
mutant NSCLC PDX models [DFCI359 (
exon19 755_757LREdelinsRP) and DFCI315 (
exon20 V777_G778insGSP)] and used the PDX tumors to generate XDOTS. Tumor spheroids were grown in a microfluidic device and treated
with neratinib-based drug combinations. Live/dead quantification was performed by dual-labeling deconvolution fluorescence microscopy. The most efficacious
combination was subsequently validated
using the DFCI359 and DFCI315 PDXs and a
genetically engineered mouse model.
Both neratinib and afatinib, but not gefitinib, induced cell death in DFCI359 XDOTS. The combinations of neratinib/trastuzumab and neratinib/temsirolimus enhanced the therapeutic benefit of neratinib alone in DFCI315 and DFCI359. The combination of neratinib and trastuzumab
was more effective compared with single-agent neratinib or trastuzumab and was associated with more robust inhibition of HER2 and downstream signaling.
The XDOTS platform can be used to evaluate therapies and therapeutic combinations
using PDX tumors. This approach may accelerate the identification and clinical development of therapies for targets with no or few existing models and/or therapies.