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Pharmacogenomic analysis of patient-derived tumor cells in gynecologic cancers.

ABSTRACT: BACKGROUND:Gynecologic malignancy is one of the leading causes of mortality in female adults worldwide. Comprehensive genomic analysis has revealed a list of molecular aberrations that are essential to tumorigenesis, progression, and metastasis of gynecologic tumors. However, targeting such alterations has frequently led to treatment failures due to underlying genomic complexity and simultaneous activation of various tumor cell survival pathway molecules. A compilation of molecular characterization of tumors with pharmacological drug response is the next step toward clinical application of patient-tailored treatment regimens. RESULTS:Toward this goal, we establish a library of 139 gynecologic tumors including epithelial ovarian cancers (EOCs), cervical, endometrial tumors, and uterine sarcomas that are genomically and/or pharmacologically annotated and explore dynamic pharmacogenomic associations against 37 molecularly targeted drugs. We discover lineage-specific drug sensitivities based on subcategorization of gynecologic tumors and identify TP53 mutation as a molecular determinant that elicits therapeutic response to poly (ADP-Ribose) polymerase (PARP) inhibitor. We further identify transcriptome expression of inhibitor of DNA biding 2 (ID2) as a potential predictive biomarker for treatment response to olaparib. CONCLUSIONS:Together, our results demonstrate the potential utility of rapid drug screening combined with genomic profiling for precision treatment of gynecologic cancers.

SUBMITTER: Sa JK

PROVIDER: S-EPMC6880425 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Pharmacogenomic analysis of patient-derived tumor cells in gynecologic cancers.

Sa Jason K JK Hwang Jae Ryoung JR Cho Young-Jae YJ Ryu Ji-Yoon JY Choi Jung-Joo JJ Jeong Soo Young SY Kim Jihye J Kim Myeong Seon MS Paik E Sun ES Lee Yoo-Young YY Choi Chel Hun CH Kim Tae-Joong TJ Kim Byoung-Gie BG Bae Duk-Soo DS Lee Yeri Y Her Nam-Gu NG Shin Yong Jae YJ Cho Hee Jin HJ Kim Ja Yeon JY Seo Yun Jee YJ Koo Harim H Oh Jeong-Woo JW Lee Taebum T Kim Hyun-Soo HS Song Sang Yong SY Bae Joon Seol JS Park Woong-Yang WY Han Hee Dong HD Ahn Hyung Jun HJ Sood Anil K AK Rabadan Raul R Lee Jin-Ku JK Nam Do-Hyun DH Lee Jeong-Won JW

Genome biology 20191126 1

<h4>Background</h4>Gynecologic malignancy is one of the leading causes of mortality in female adults worldwide. Comprehensive genomic analysis has revealed a list of molecular aberrations that are essential to tumorigenesis, progression, and metastasis of gynecologic tumors. However, targeting such alterations has frequently led to treatment failures due to underlying genomic complexity and simultaneous activation of various tumor cell survival pathway molecules. A compilation of molecular chara ...[more]

PMID: 31771620

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Project description:Malignant tumors derived from the epithelium lining the nasal cavity region are termed sinonasal cancers, a highly heterogeneous group of rare tumors accounting for 3 - 5 % of all head and neck cancers. Progress with next-generation molecular profiling has improved our understanding of the complexity of sinonasal cancers and resulted in the identification of an increasing number of distinct tumor entities. Despite these significant developments, the treatment of sinonasal cancers has hardly evolved since the 1980s, and an advanced sinonasal cancer presents a poor prognosis as targeted therapies are usually not available. To gain insights into potential targeted therapeutic opportunities, we performed a multiomics profiling of patient-derived functional tumor models to identify molecular characteristics associated with pharmacological responses in the different subtypes of sinonasal cancer.MethodsPatient-derived ex vivo tumor models representing four distinct sinonasal cancer subtypes: sinonasal intestinal-type adenocarcinoma, sinonasal neuroendocrine carcinoma, sinonasal undifferentiated carcinoma and SMARCB1 deficient sinonasal carcinoma were included in the analyses. Results of functional drug screens of 160 anti-cancer therapies were integrated with gene panel sequencing and histological analyses of the tumor tissues and the ex vivo cell cultures to establish associations between drug sensitivity and molecular characteristics including driver mutations.ResultsThe different sinonasal cancer subtypes display considerable differential drug sensitivity. Underlying the drug sensitivity profiles, each subtype was associated with unique molecular features. The therapeutic vulnerabilities correlating with specific genomic background were extended and validated with in silico analyses of cancer cell lines representing different human cancers and with reported case studies of sinonasal cancers treated with targeted therapies.ConclusionThe results demonstrate the importance of understanding the differential biology and the molecular features associated with the different subtypes of sinonasal cancers. Patient-derived ex vivo tumor models can be a powerful tool for investigating these rare cancers and prioritizing targeted therapeutic strategies for future clinical development and personalized medicine.

Dataset Information

Pharmacogenomic analysis of patient-derived tumor cells in gynecologic cancers.

Publications

Pharmacogenomic analysis of patient-derived tumor cells in gynecologic cancers.

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