The taxane family of chemotherapy drugs has been used to treat a variety of mostly epithelial-derived tumors and remain the first-line treatment for some cancers. Despite the improved survival time and reduction of tumor size observed in some patients, many have no response to the drugs or develop resistance over time. Taxane resistance is multi-faceted and involves multiple pathways in proliferation, apoptosis, metabolism, and the transport of foreign substances. In this review, we dive deeper into hypothesized resistance mechanisms from research during the last decade, with a focus on the cancer types that use taxanes as first-line treatment but frequently develop resistance to them. Furthermore, we will discuss current clinical inhibitors and those yet to be approved that target key pathways or proteins and aim to reverse resistance in combination with taxanes or individually. Lastly, we will highlight taxane response biomarkers, specific genes with monitored expression and correlated with response to taxanes, mentioning those currently being used and those that should be adopted. The future directions of taxanes involve more personalized approaches to treatment by tailoring drug–inhibitor combinations or alternatives depending on levels of resistance biomarkers. We hope that this review will identify gaps in knowledge surrounding taxane resistance that future research or clinical trials can overcome.
Adenomatous Polyposis Coli (APC) is lost in approximately 70% of sporadic breast cancers, with an inclination towards triple negative breast cancer (TNBC). TNBC is treated with traditional chemotherapy, such as paclitaxel (PTX); however, tumors often develop drug resistance. We previously created APC knockdown cells (APC shRNA1) using the human TNBC cells, MDA-MB-157, and showed that APC loss induces PTX resistance. To understand the mechanisms behind APC-mediated PTX response, we performed cell cycle analysis and analyzed cell cycle related proteins. Cell cycle analysis indicated increased G2/M population in both PTX-treated APC shRNA1 and parental cells, suggesting that APC expression does not alter PTX-induced G2/M arrest. We further studied the subcellular localization of the G2/M transition proteins, cyclin B1 and CDK1. The APC shRNA1 cells had increased CDK1, which was preferentially localized to the cytoplasm, and increased baseline CDK6. RNA-sequencing was performed to gain a global understanding of changes downstream of APC loss and identified a broad mis-regulation of cell cycle-related genes in APC shRNA1 cells. Our studies are the first to show an interaction between APC and taxane response in breast cancer. The implications include designing combination therapy to re-sensitize APC-mutant breast cancers to taxanes using the specific cell cycle alterations.
Adenomatous Polyposis Coli (APC) is lost in approximately 70% of sporadic breast cancers, with an inclination towards triple negative breast cancer (TNBC). TNBC is treated with traditional chemotherapy, such as paclitaxel (PTX); however, tumors often develop drug resistance. We previously created APC knockdown cells (APC shRNA1) using the human TNBC cells, MDA-MB-157, and showed that APC loss induces PTX resistance. To understand the mechanisms behind APC-mediated PTX response, we performed cell cycle analysis and analyzed cell cycle related proteins. Cell cycle analysis indicated increased G2/M population in PTX-treated APC shRNA1 cells compared to PTX-treated controls, suggesting that APC expression does not alter PTX-induced G2/M arrest. We further studied the subcellular localization of the G2/M transition proteins, cyclin B1 and CDK1. The APC shRNA1 cells had increased CDK1, which was preferentially localized to the cytoplasm, and increased CDK6. RNA-sequencing was performed to gain a global understanding of changes downstream of APC loss and identified a broad mis-regulation of cell cycle-related genes in APC shRNA1 cells. Our studies are the first to show an interaction between APC and taxane response in breast cancer. The implications include designing combination therapy to re-sensitize APC-mutant breast cancers to taxanes using the specific cell cycle alterations.
Adenomatous Polyposis Coli (APC) is a multi-domain tumor suppressor with multiple binding partners, including β-catenin, axin, and microtubules. APC is lost in many epithelial cancers, including up to 70% of sporadic breast cancers, with a tendency towards triple negative breast cancers (TNBCs). We previously demonstrated that APC knockdown in the human TNBC cell line, MDA-MB-157, resulted in resistance to Paclitaxel (PTX), a chemotherapeutic agent of the Taxane family that inhibits mitotic progression. Further studies have confirmed this finding in the MDA-MB-231 cells with CRISPR-mediated APC knockout. To understand the mechanism(s) by which APC controls response to PTX, we have taken two approaches. We first performed an unbiased analysis of transcriptomic changes downstream of APC loss to identify potential therapeutic targets to overcome PTX resistance. In this, a group of transcripts involved in regulation of the cell cycle were identified, including LBH, GLI1, RGS4, and NUPR1. These results have been validated by qRT-PCR and western blot, leading to studies in the laboratory to investigate their specific effects on the response to PTX in breast cancer. Along with the broad exploration studies, molecular studies have focused on whether APC controls expression of cell cycle proteins, leading to PTX resistance. While we observed changes in multiple cell cycle proteins, our focus was on the G2/M transition, given that both PTX and APC impact microtubule dynamics and the G2/M phase of the cell cycle. We examined the effect of APC loss on expression of G2/M proteins, identifying a significant upregulation of CDK1 in APCKD cells. Despite no changes in phosphorylation status of CDK1, we found that Cyclin B1 and CDK1 are only complexed in the APCKD cells, suggesting increased activation. Further studies showed that while the majority of CDK1 and Cyclin B1 are localized to the cytoplasm, there is a small amount in the nucleus. Based on these findings, we sought to investigate whether PTX sensitivity would be altered in response to CDK1 inhibitor, RO-3306. We have shown that PTX resistant APCKD cells are more sensitive (IC50 = 25.5uM) to RO-3306 compared the parental control (IC50 = 78uM). Future studies will use combination and sequential treatments to monitor PTX response in vitro and in vivo. Combined, these studies are elucidating the mechanisms by which loss of APC controls sensitivity to PTX in TNBC, with the long-term goal of designing treatment regimens to improve patient health and survival. Citation Format: Jeni Prosperi, Emily Astarita, Camden Hoover, Sara Maloney. Apc control of taxane resistance in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-21.
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