Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy.

Abstract

Outcomes of anticancer therapy vary dramatically among patients due to diverse genetic and molecular backgrounds, highlighting extensive intertumoral heterogeneity. The fundamental tenet of precision oncology defines molecular characterization of tumors to guide optimal patient-tailored therapy. Towards this goal, we have established a compilation of pharmacological landscapes of 462 patient-derived tumor cells (PDCs) across 14 cancer types, together with genomic and transcriptomic profiling in 385 of these tumors. Compared with the traditional long-term cultured cancer cell line models, PDCs recapitulate the molecular properties and biology of the diseases more precisely. Here, we provide insights into dynamic pharmacogenomic associations, including molecular determinants that elicit therapeutic resistance to EGFR inhibitors, and the potential repurposing of ibrutinib (currently used in hematological malignancies) for EGFR-specific therapy in gliomas. Lastly, we present a potential implementation of PDC-derived drug sensitivities for the prediction of clinical response to targeted therapeutics using retrospective clinical studies.

• Authors: Jin-Ku Lee, Zhaoqi Liu, Jason K Sa, Sang Shin, Jiguang Wang, Mykola Bordyuh, Hee Jin Cho, Oliver Elliott, Timothy Chu, Seung Won Choi, Daniel I S Rosenbloom, In-Hee Lee, Yong Jae Shin, Hyun Ju Kang, Donggeon Kim, Sun Young Kim, Moon-Hee Sim, Jusun Kim, Taehyang Lee, Yun Jee Seo, Hyemi Shin, Mijeong Lee, Sung Heon Kim, Yong-Jun Kwon, Jeong-Woo Oh, Minsuk Song, Misuk Kim, Doo-Sik Kong, Jung Won Choi, Ho Jun Seol, Jung-Il Lee, Seung Tae Kim, Joon Oh Park, Kyoung-Mee Kim, Sang-Yong Song, Jeong-Won Lee, Hee-Cheol Kim, Jeong Eon Lee, Min Gew Choi, Sung Wook Seo, Young Mog Shim, Jae Ill Zo, Byong Chang Jeong, Yeup Yoon, Gyu Ha Ryu, Nayoung K D Kim, Joon Seol Bae, Woong-Yang Park, Jeongwu Lee, Roel G W Verhaak, Antonio Iavarone, Jeeyun Lee, Raul Rabadan, Do-Hyun Nam
• Journal: Nature genetics (Nat Genet) Vol. 50 Issue 10 Pg. 1399-1411 (10 2018) ISSN: 1546-1718 [Electronic] United States
• PMID: 30262818 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Pharmacological
• Biomarkers, Tumor
• Panobinostat

Topics

• Antineoplastic Agents (classification, isolation & purification, therapeutic use)
• Biomarkers, Pharmacological (analysis)
• Biomarkers, Tumor (analysis, genetics)
• Cell Lineage (drug effects, genetics)
• Drug Resistance, Neoplasm (genetics)
• Drug Screening Assays, Antitumor
• Feasibility Studies
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• Humans
• Medical Oncology (methods)
• Molecular Targeted Therapy
• Neoplasms (drug therapy, genetics, pathology)
• Panobinostat (therapeutic use)
• Patient-Centered Care (methods)
• Pharmacogenetics (methods)
• Precision Medicine (methods)
• Primary Cell Culture (methods)
• Tumor Cells, Cultured