Development of Novel Patient-Derived Preclinical Models from Malignant Effusions in Patients with Tyrosine Kinase Inhibitor-Resistant Clear Cell Renal Cell Carcinoma.
OBJECTIVE
Although targeting angiogenesis with tyrosine kinase inhibitors (TKIs) has become standard of care in the treatment of clear cell renal cell carcinoma (RCC), resistance mechanism are not fully understood, and there is a need to develop new therapeutic options overcoming them.


METHODS
To develop a preclinical model that predicts clinical activity of novel agents in 19 RCC patients, we established patient-derived cell (PDC) and xenograft (PDX) models derived from malignant effusions or surgical specimen.


RESULTS
Successful PDCs, defined as cells that maintained growth following two passages, were established in 5 of 15 malignant effusions and 1 of 4 surgical specimens. One PDC, clinically refractory to TKIs, was implanted and engrafted in mice, resulting in a comparable histology to the primary tumor. The PDC-PDX model also showed similar genomic features when tested using targeted sequencing of cancer-related genes. When we examined the drug effects of the PDX model, the tumor cells showed resistance to TKIs and everolimus in vitro.


CONCLUSIONS
The results suggest that the PDC-PDX preclinical model we developed using malignant effusions can be a useful preclinical model to interrogate sensitivity to targeted agents based on genomic alterations.
Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
Jiryeon
J
Jang
Oncotest GmbH, Freiburg, Germany.
Oliver
O
Rath
Oncotest GmbH, Freiburg, Germany.
Julia
J
Schueler
Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
Hyun Hwan
HH
Sung
Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
Hwang Gyun
HG
Jeon
Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
Byong Chang
BC
Jeong
Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
Seong Il
SI
Seo
Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
Seong Soo
SS
Jeon
Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea. Electronic address: besthml@skku.edu.
Hyun Moo
HM
Lee
Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
Han-Yong
HY
Choi
Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
Ghee-Young
GY
Kwon
Samsung Genome Institute, Seoul, Republic of Korea.
Woong Yang
WY
Park
Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
Jeeyun
J
Lee
Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea. Electronic address: hematoma@skku.edu.
Se Hoon
SH
Park