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posted on 2023-03-31, 21:03 authored by Elena Ivanova, Mari Kuraguchi, Man Xu, Andrew J. Portell, Luke Taus, Irmina Diala, Alshad S. Lalani, Jihyun Choi, Emily S. Chambers, Shuai Li, Shengwu Liu, Ting Chen, Thanh U. Barbie, Geoffrey R. Oxnard, Jacob J. Haworth, Kwok-Kin Wong, Suzanne E. Dahlberg, Amir A. Aref, David A. Barbie, Magda Bahcall, Cloud P. Paweletz, Pasi A. Jänne Supplemental Figure 1. Characterization of DFCI 359 and DFCI 315.
Funding
NCI
NIH
The American Cancer Society
Expect Miracles Foundation
the Robert and René Belfer Foundation
History
ARTICLE ABSTRACT
Evaluating drug responses using primary patient-derived cells ex vivo represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib combinations in HER2 mutant non–small cell lung cancer (NSCLC) patient xenograft-derived organotypic spheroids (XDOTS) using a short-term ex vivo system.
We generated two HER2-mutant NSCLC PDX models [DFCI359 (HER2 exon19 755_757LREdelinsRP) and DFCI315 (HER2 exon20 V777_G778insGSP)] and used the PDX tumors to generate XDOTS. Tumor spheroids were grown in a microfluidic device and treated ex vivo with neratinib-based drug combinations. Live/dead quantification was performed by dual-labeling deconvolution fluorescence microscopy. The most efficacious ex vivo combination was subsequently validated in vivo using the DFCI359 and DFCI315 PDXs and a HER2YVMA 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 in vivo 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 ex vivo 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.
