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Utility of patient-derived lymphoblastoid cell lines as an ex vivo capecitabine sensitivity prediction model for breast cancer patients.

ABSTRACT: Capecitabine is commonly used in treating breast cancer; however, therapeutic response varies among patients and there is no clinically validated model to predict individual outcomes. Here, we investigated whether drug sensitivity quantified in ex vivo patients' blood-derived cell lines can predict response to capecitabine in vivo. Lymphoblastoid cell lines (LCLs) were established from a cohort of metastatic breast cancer patients (n = 53) who were prospectively monitored during treatment with single agent capecitabine at 2000 mg/m2/day. LCLs were treated with increasing concentrations of 5'-DFUR, a major capecitabine metabolite, to assess patients' ex vivo sensitivity to this drug. Subsequently, ex vivo phenotype was compared to observed patient disease response and drug induced-toxicities. We acquired an independent cohort of breast cancer cell lines and LCLs derived from the same donors from ATCC, compared their sensitivity to 5'-DFUR. As seen in the patient population, we observed large inter-individual variability in response to 5'-DFUR treatment in patient-derived LCLs. Patients whose LCLs were more sensitive to 5'-DFUR had a significantly longer median progression free survival (9-month vs 6-month, log rank p-value = 0.017). In addition, this significant positive correlation for 5'-DFUR sensitivity was replicated in an independent cohort of 8 breast cancer cell lines and LCLs derived from the same donor. Our data suggests that at least a portion of the individual sensitivity to capecitabine is shared between germline tissue and tumor tissue. It also supports the utility of patient-derived LCLs as a predictive model for capecitabine treatment efficacy in breast cancer patients.

SUBMITTER: Morrison G

PROVIDER: S-EPMC5122395 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Utility of patient-derived lymphoblastoid cell lines as an ex vivo capecitabine sensitivity prediction model for breast cancer patients.

Morrison Gladys G Lenkala Divya D LaCroix Bonnie B Ziliak Dana D Abramson Vandana V Morrow Phuong Khanh PK Forero Andres A Van Poznak Catherine C Rugo Hope S HS Nanda Rita R O'Donnell Peter H PH Huang R Stephanie RS

Oncotarget 20160601 25

Capecitabine is commonly used in treating breast cancer; however, therapeutic response varies among patients and there is no clinically validated model to predict individual outcomes. Here, we investigated whether drug sensitivity quantified in ex vivo patients' blood-derived cell lines can predict response to capecitabine in vivo. Lymphoblastoid cell lines (LCLs) were established from a cohort of metastatic breast cancer patients (n = 53) who were prospectively monitored during treatment with s ...[more]

PMID: 27224917

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Project description:We used mass spectrometry-based proteomics to perform a phosphoproteomics analysis of selinexor-treated ex vivo AML patient samples (n=20) and 4 AML cell lines (PL-21, NOMO-1, GDM-1 and MV4-11). For quantitative phosphoproteomics, we used a tandem mass tag (TMT)-based approach. Conditions for the TMT 11-plex (Ex vivo samples) and TMT 8-plex (AML cell lines) setups are specified below. Cells were treated with 1 M selinexor (also known as KPT-330) or 0.1% DMSO for 6 hours. The experimental treatment conditions and TMT11-plex (ex vivo samples) and TMT8-plex (cell lines) labeling schemes are specified below: TMT-11-plex TMT channel Patient no Treatment Set 1 126 Ex_24 DMSO Set 1 127N Ex_24 Selinexor Set 1 127C Ex_25 DMSO Set 1 128N Ex_25 Selinexor Set 1 128C Ex_34 DMSO Set 1 129N Ex_34 Selinexor Set 1 129C Ex_41 DMSO Set 1 130N Ex_41 Selinexor Set 1 130C Ex_44 DMSO Set 1 131N Ex_44 Selinexor Set 1 131C Mix pool Mix pool Set 2 126 Ex_9 DMSO Set 2 127N Ex_9 Selinexor Set 2 127C Ex_18 DMSO Set 2 128N Ex_18 Selinexor Set 2 128C Ex_27 DMSO Set 2 129N Ex_27 Selinexor Set 2 129C Ex_29 DMSO Set 2 130N Ex_29 Selinexor Set 2 130C Ex_36 DMSO Set 2 131N Ex_36 Selinexor Set 2 131C Mix pool Mix pool Set 3 126 Ex_8 DMSO Set 3 127N Ex_8 Selinexor Set 3 127C Ex_13 DMSO Set 3 128N Ex_13 Selinexor Set 3 128C Ex_14 DMSO Set 3 129N Ex_14 Selinexor Set 3 129C Ex_19 DMSO Set 3 130N Ex_19 Selinexor Set 3 130C Ex_40 DMSO Set 3 131N Ex_40 Selinexor Set 3 131C Mix pool Mix pool Set 4 126 Ex_6 DMSO Set 4 127N Ex_6 Selinexor Set 4 127C Ex_15 DMSO Set 4 128N Ex_15 Selinexor Set 4 128C Ex_28 DMSO Set 4 129N Ex_28 Selinexor Set 4 129C Ex_39 DMSO Set 4 130N Ex_39 Selinexor Set 4 130C Ex_42 DMSO Set 4 131N Ex_42 Selinexor Set 4 131C Mix pool Mix pool AML cell lines: TMT-8-plex TMT channel Treatment Replicate GDM-1 126 DMSO 1 GDM-1 127N DMSO 2 GDM-1 127C DMSO 3 GDM-1 128N DMSO 4 GDM-1 128C Selinexor 1 GDM-1 129N Selinexor 2 GDM-1 129C Selinexor 3 GDM-1 130N Selinexor 4 MV4-11 126 DMSO 1 MV4-11 127N DMSO 2 MV4-11 127C DMSO 3 MV4-11 128N DMSO 4 MV4-11 128C Selinexor 1 MV4-11 129N Selinexor 2 MV4-11 129C Selinexor 3 MV4-11 130N Selinexor 4 NOMO-1 126 DMSO 1 NOMO-1 127N DMSO 2 NOMO-1 127C DMSO 3 NOMO-1 128N DMSO 4 NOMO-1 128C Selinexor 1 NOMO-1 129N Selinexor 2 NOMO-1 129C Selinexor 3 NOMO-1 130N Selinexor 4 PL-21 126 DMSO 1 PL-21 127N DMSO 2 PL-21 127C DMSO 3 PL-21 128N DMSO 4 PL-21 128C Selinexor 1 PL-21 129N Selinexor 2 PL-21 129C Selinexor 3 PL-21 130N Selinexor 4

Dataset Information

Utility of patient-derived lymphoblastoid cell lines as an ex vivo capecitabine sensitivity prediction model for breast cancer patients.

Publications

Utility of patient-derived lymphoblastoid cell lines as an ex vivo capecitabine sensitivity prediction model for breast cancer patients.

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