Capecitabine Efficacy Is Correlated with TYMP and RB1 Expression in PDX Established from Triple-Negative Breast Cancers

Abstract

Triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines- and taxanes-based treatments. PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins, and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistologic analysis. Downregulation of was performed by siRNA in a cell line established from a PDX. Residual TNBC PDX were characterized by a high tumor take, a short latency, and a poor prognosis of the corresponding patients. With the exception of BRCA1/2-mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX, with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naïve derived tumors, identified RB1 and TYMP proteins as predictive biomarkers for capecitabine response. Finally, knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment. We identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes, and platins. RB1 positivity and high expression of TYMP were significantly associated with capecitabine response. .

Quantitative analysis of differentially expressed proteins in psoriasis vulgaris using tandem mass tags and parallel reaction monitoring

“…MPO has been proven to play a key role in aggravating the inflammatory response and tissue damage in PV patients. In addition, TYMP has been demonstrated to directly stimulate the expression of angiogenic factors such as VEGF, TNFα, and IL-8 [18] as well as promote angiogenesis [19,20]. Moreover, IMPDH2, which is synthesized by guanine nucleotide rate-limiting enzymes, provides guanine nucleotides for T cell proliferation [21,22] and is highly expressed in proliferating tumor tissues [23].…”

A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer

“…Sixty‐one PDXs were obtained from the engraftment of 150 early‐stage triple‐negative breast tumors or axillary lymph node metastases excised from patients between 2000 and 2017 with their informed consent . Forty of the 61 established TNBC PDXs were obtained from primary breast cancer, 19 were obtained from residual disease after neoadjuvant chemotherapy and 2 were obtained from primary axillary nodes (Supporting Information Tables S1 and S2).…”

Quantitative analysis of differentially expressed proteins in psoriasis vulgaris using tandem mass tags and parallel reaction monitoring

“…MPO has been proven to play a key role in aggravating the in ammatory response and tissue damage in PV patients. In addition, TYMP has been demonstrated to directly stimulate the expression of angiogenic factors such as VEGF, TNFα, and IL-8 [18] as well as promote angiogenesis [19,20]. Moreover, IMPDH2, which is synthesized by guanine nucleotide rate-limiting enzymes, provides guanine nucleotides for T cell proliferation [21,22] and is highly expressed in proliferating tumor tissues [23].…”