An in vivo genome‐wide shRNA screen identifies BCL6 as a targetable biomarker of paclitaxel resistance in breast cancer

Abstract

Paclitaxel is a common breast cancer drug; however, some tumors are resistant. The identification of biomarkers for paclitaxel resistance or sensitivity would enable the development of strategies to improve treatment efficacy. A genome-wide in vivo shRNA screen was performed on paclitaxel-treated mice with MDA-MB-231 tumors to identify genes associated with paclitaxel sensitivity or resistance. Gene expression of the top screen hits was associated with tumor response (resistance or sensitivity) among patients who received neoadjuvant chemotherapy containing paclitaxel. We focused our validation on screen hit B-cell lymphoma 6 (BCL6), which is a therapeutic target in cancer but for which no effects on drug response have been reported. Knockdown of BCL6 resulted in increased tumor regression in mice treated with paclitaxel. Similarly, inhibiting BCL6 using a small molecule inhibitor enhanced paclitaxel treatment efficacy both in vitro and in vivo in breast cancer models. Mechanism studies revealed that reduced BCL6 enhances the efficacy of paclitaxel by inducing sustained G1/S arrest, concurrent with increased apoptosis and expression of target gene cyclindependent kinase inhibitor 1A. In summary, the genome-wide shRNA knockdown screen has identified BCL6 as a potential targetable resistance biomarker of paclitaxel response in breast cancer.

Metabolic Engineering of Saccharomyces cerevisiae for Heterologous Carnosic Acid Production

“…Naturally occurring cyclic diterpenoids, such as tanshinones, paclitaxel, or platensimycin, possess antimicrobial and antitumor activities. Among them, paclitaxel has been extensively used as an anticancer drug ( Vranová et al, 2013 ; Sultan et al, 2021 ). Ginkgo lactone can be used to treat cardiovascular disease as a natural platelet activation antagonist ( Liu et al, 2018 ) and is also employed to treat Alzheimer’s disease ( Sarkar et al, 2020 ).…”

BCL6 is a context-dependent mediator of the glioblastoma therapy response

“…308 BCL6 expression has also been linked to paclitaxel resistance in breast cancer. 309 ChIP-seq for BCL6 in breast cancer cell lines revealed a different pattern of binding to that seen in GC B cells and lymphoma. 307 Around 50% of the genes bound by BCL6 in breast cancer were also bound by BCL6 in lymphoma, indicating at least some overlap in BCL6 function.…”

“…Previous studies have shown that BCL6 is involved in resistance to several types of anti-cancer therapies in multiple cancers. 207,210,295,302,309,311,350,351,406 In GBM cell lines, inhibition of BCL6 significantly increases the efficacy of TMZ and IR. 207,210 However, little was known about how BCL6 is involved in these therapy responses.…”

“…3,[347][348][349] Previous studies have linked BCL6 to the therapy resistance of GBM and other cancer types. 207,210,302,309,310,[350][351][352][353][354] This suggests that BCL6 may be a promising target to improve the efficacy of GBM therapies. The aim of this study was to gain a broad understanding of how GBM cells respond to therapy and to investigate how BCL6 activity is involved in this response.…”