Abstract P3-03-02: Integrative proteogenomic analyses identifies CPT1A and fatty acid oxidation as a potential therapeutic strategy in hormone receptor positive breast cancer
Authors: Gatza Michael L , Bhatt Vrushank , Parker Kimberly , Mehta Guarav , Khella Christen , Guo Yanxiang , Jariwala Nidhi 
Published: March 2020

Background: Clinically, approximately two-thirds of the nearly 250,000 breast cancer cases diagnosed each year in the United States are hormone receptor positive (HR+), luminal breast tumors. Slower growing luminal breast tumors are often successfully treated using endocrine based therapies resulting in a relatively good prognosis for these patients. However more highly proliferative luminal tumors are often resistant, or become resistant, to current therapies leading to a worse outcome for these patients. As such, there is a critical need to identify genomic alterations and dysregulated signaling pathway in this subset of tumors that may represent novel therapeutic opportunities. Methods: In order to identify genetic events responsible for tumorigenesis and to identify potential drug-able genetic alterations and/or pathways associated with high levels of proliferation in HR+ tumors, we used an integrative genomics-based strategy to interrogate orthogonal genome-wide data from more than 2,500 patients from the TCGA, METABRIC, CPTAC studies. Data from a genome-wide RNAi screen was used to delineate essential from non-essential genes in HR+ breast cancer cell lines. Genetic and pharmacological-based in vitro and in vivo studies were used to demonstrate the impact identified candidate genes on cell viability, proliferation, colony formation, spheroid formation and tumor growth rate. Results: Integrative genomic analyses of human breast tumors identified DNA amplification as well as mRNA and protein over-expression of carnitine palmitoyltransferase 1A (CPT1A) in highly proliferative luminal tumors. Further in silico analyses demonstrated that high CPT1A expression corresponded with protein markers of proliferation in human tumors and is prognostic in HR+ tumors in both the TCGA and METABRIC cohorts. Since CPT1A is the rate limiting enzyme responsible for fatty acid import into the mitochondria during Fatty Acid β Oxidation (FAO), these data indicate that highly proliferative luminal tumors may utilize FAO as a prominent energy source. As such, we hypothesized that inhibiting CPT1A and/or FAO in this subset of tumors or cell lines may represent a potential therapeutic opportunity. Consistent with our hypothesis, analyses of data from a genome-wide RNAi screen in 27 breast cancer cell lines suggested that HR+ cells lines are dependent on CPT1A expression. Importantly, we experimentally demonstrated that in vitro genetic silencing of CPT1A or pharmacological inhibition of FAO in ER+ breast cancer cell lines results in reduced cell viability and increased cell death as well as decreased spheroid formation. Importantly, our data indicated that in vivo inhibition of CPT1A resulted in decreased tumor volume and growth rate in orthotopic xenograft tumor models. Conclusions: In this study, integrative proteogenomic analyses identified amplification and over-expression of CPT1A in highly proliferative ER+ breast tumors. In vitro and in vivo studies demonstrated that CPT1A is an essential oncogenic driver in HR+/luminal breast cancer and establish CTP1A/FAO inhibition as a putative therapeutic strategy for treatment of these tumors.

Citation Format: Michael L Gatza, Vrushank Bhatt, Kimberly Parker, Guarav Mehta, Christen Khella, Yanxiang Guo, Nidhi Jariwala. Integrative proteogenomic analyses identifies CPT1A and fatty acid oxidation as a potential therapeutic strategy in hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-02.