延缓紫杉烷类化疗药的耐药

一、memantine 美金刚胺
% s! F/ L5 y$ c# Q) Q1、美金刚胺抑制 tau 、 stathmin，给紫杉烷增敏增效
《The cytotoxic effect of memantine and its effect on cytoskeletal proteins expression in metastatic breast cancer cell line》
4 z' v7 W; v4 |- G$ JResults: Incubation of breast cancer cells with memantine resulted in a dose dependent reduction in cell survival (P=0.0001). Paclitaxel (100 nM) showed synergistic effect with memantine (P=0.0001). Memantine significantly decreased tau and stathmin mRNA expression (by RT-PCR), so that 100 µmol/l of memantine decreased tau and stathmin expression by 46% (P=0.0341) and 33% (P=0.043), respectively. Migration of cells was also decreased by memantine (P=0.0001).

  h7 \0 f' o' r8 g) a$ E; ^2、紫杉醇的主要副作用之一是引起神经病理性疼痛。紫杉醇治疗通过蛋白激酶C诱导脊髓中突触前NMDARs的紧张性激活，以加强初级传入神经的伤害性输入。在脊髓水平靶向突触前NMDARs可能是治疗化疗诱导的神经病理性疼痛的有效策略。美金刚胺是 NMDAR 拮抗剂。美金刚胺也做过临床试验能缓解乳腺癌患者手术、化疗带来的神经疼痛。
（1）《Presynaptic N-Methyl-d-aspartate (NMDA) Receptor Activity Is Increased Through Protein Kinase C in Paclitaxel-induced Neuropathic Pain》
In addition, intrathecal injection of AP5 or systemic administration of memantine profoundly attenuated pain hypersensitivity induced by paclitaxel. Our findings indicate that paclitaxel treatment induces tonic activation of presynaptic NMDARs in the spinal cord through protein kinase C to potentiate nociceptive input from primary afferent nerves. Targeting presynaptic NMDARs at the spinal cord level may be an effective strategy for treating chemotherapy-induced neuropathic pain.
# S9 p+ E( M$ d2 b7 {4 R3 @（2）《Memantine before Mastectomy Prevents Post-Surgery Pain: A Randomized, Blinded Clinical Trial in Surgical Patients》
Conclusions: This study shows for the first time the beneficial effect of memantine to prevent post-mastectomy pain development and to diminish chemotherapy-induced pain symptoms. The lesser analgesic consumption and better well-being of patients for at least six months after treatment suggests that memantine could be an interesting therapeutic option to diminish the burden of breast cancer therapy.

2 _0 C& r) O& p; i" L! n二、萝卜硫素+木犀草素
" O- [% B) M  A% dβIII-tubulin 的高表达是包含紫杉烷类药物在内的微管靶向剂耐药的主要原因之一（ER阴性的乳腺癌、卵巢癌除外）。
直接抑制βIII-tubulin的药物非常难找，只有 Sulforaphane 萝卜硫素有一定的可能性和可及性。
: z: w' J( O  V7 ]$ B: [( }$ ~0 Z但萝卜硫素是NRF2的激活剂，NRF2的高表达也是大多数抗癌药耐药的主要原因之一。用萝卜硫素应该同时联用NRF2抑制剂 Luteolin木犀草素等药物。木犀草素本身对微管靶向剂也有增敏增效的作用。
1、Sulforaphane 萝卜硫素对 βIII-tubulin 有一定的抑制作用。
《Sulforaphane metabolites reduce resistance to paclitaxel via microtubule disruption》
Long treatment with paclitaxel (PTX) might increase resistance and side-effects causing a failure in cancer chemotherapy. Here we uncovered that either sulforaphane-cysteine (SFN-Cys) or sulforaphane-N-acetyl-cysteine (SFN-NAC) induced apoptosis via phosphorylated ERK1/2-mediated upregulation of 26 S proteasome and Hsp70, and downregulation of βIII-tubulin, XIAP, Tau, Stathmin1 and α-tubulin causing microtubule disruption in human PTX-resistant non-small cell lung cancer (NSCLC) cells. Knockdown of either βIII-tubulin or α-tubulin via siRNA increased cell sensitivity to PTX, indicating that these two proteins help cells increase the resistance. Tissue microarray analysis showed that overexpression of βIII-tubulin correlated to NSCLC malignant grading. Immunofluorescence staining also showed that SFN metabolites induced a nest-like microtubule protein distribution with aggregation and disruption. Co-immunoprecipitation showed that SFN metabolites reduced the interaction between βIII-tubulin and Tau, and that between α-tubulin and XIAP. The combination of PTX with SFN metabolites decreased the resistance to PTX, and doses of both PTX and SFN metabolites, and enhanced apoptosis resulting from activated Caspase-3-caused microtubule degradation. Importantly, the effective dose of SFN metabolites combined with 20 nM PTX will be low to 4 μM. Thus, we might combine SFN metabolites with PTX for preclinical trial. Normally, more than 20 μM SFN metabolites only leading to apoptosis for SFN metabolites hindered their applications. These findings will help us develop a low-resistance and high-efficiency chemotherapy via PTX/SFN metabolites combination.
/ _" Y9 {6 G; G. \+ w
3 \3 D! S; i9 P2 V% s2、萝卜硫素抗癌做过前瞻性对照临床试验，有一定的作用；可以在这个临床试验的基础上再改进。
- f3 O# \' {1 W, c( {4 H; N《Broccoli sprout supplementation in patients with advanced pancreatic cancer is difficult despite positive effects—results from the POUDER pilot study》
Pancreatic ductal adenocarcinoma is a highly aggressive malignancy with short survival and limited therapeutic options. Broccoli sulforaphane is a promising new treatment due to the results of recent epidemiological, experimental and patient studies. Upon approval from the ethics committee and registration at ClinicalTrials.gov, 40 patients with palliative chemotherapy were placed into a placebo and treatment group in an unblinded fashion. Fifteen capsules with pulverized broccoli sprouts containing 90 mg/508 μmol sulforaphane and 180 mg/411 μmol glucoraphanin or methylcellulose were administered daily for up to 1 year. Twenty-nine patients were included in the treatment group and 11 patients were in the placebo group; these patients were followed for up to 1 year. The patient characteristics, overall survival and feasibility were assessed. Compared to those of the placebo group, the mean death rate was lower in the treatment group during the first 6 months after intake (day 30: 0%/18%, day 90: 0%/25%, and day 180: 25%/43%), and Kaplan-Meier analysis revealed a higher survival rate. There was a high drop-out rate (72% in the treatment group and 55% in the placebo group) after 1 year. We concluded from the Karnofsky index that the broccoli sprouts did not impact patient’s self-care and overall abilities severely. The intake of 15 capsules daily was difficult for some patients, and the broccoli sprouts sometimes increased digestive problems, nausea and emesis. We did not obtain statistically significant results (p = 0.291 for the endpoint at day 180), but the knowledge about the feasibility is the basis for the development of new sulforaphane drugs.
临床试验结果显示疗效有改善，但是没有达到统计学意义（p = 0.291）。
我认为没有达到统计学意义除了试验时间过短外等原因外，主要就是萝卜硫素激活了NRF2抵消了其抗癌作用。
# @. k  O6 A' C$ ?( c用萝卜硫素应该同时联用木犀草素NRF2抑制剂为宜。

3、木犀草素本身对紫杉烷等微管靶向剂也有增敏增效作用
见《Luteolin attenuates cancer cell stemness in PTX-resistant oesophageal cancer cells through mediating SOX2 protein stability》、《Luteolin enhances paclitaxel-induced apoptosis in human breast cancer MDA-MB-231 cells by blocking STAT3》、《Luteolin induces apoptosis in oral squamous cancer cells.》、《Luteolin combined with low-dose paclitaxel synergistically inhibits epithelial-mesenchymal transition and induces cell apoptosis on esophageal carcinoma in vitro and in vivo》、《Epithelial-to-Mesenchymal Transition in Paclitaxel-Resistant Ovarian Cancer Cells Is Downregulated by Luteolin》、《Suppression of Taxanes Cytotoxicity by Citrus Flavonoid Hesperetin in PPC-1 Human Prostate Cancer Cells》、《A standardized herbal extract mitigates tumor inflammation and augments chemotherapy effect of docetaxel in prostate cancer》
: S* {+ h, _3 b
三、p-gp抑制剂替代药物 他莫昔芬、阿帕替尼
7 I. {+ |7 ^) B  b* v. b紫杉醇类药物主要是p-gp的底物；抑制p-gp能增加肿瘤内紫杉醇药物的浓度，延缓耐药。目前还没有专门的p-gp靶向药上市，他莫昔芬、阿帕替尼是比较有实际可行性的p-gp抑制剂替代药物。
1、间歇性用大剂量的他莫昔芬，起到p-gp抑制的作用。
0 U6 J0 w- i) w) Q3 F1 T0 V《Efficacy of tamoxifen in combination with docetaxel in patients with advanced non-small-cell lung cancer pretreated with platinum-based chemotherapy》
3 i! h. y% c. j7 EThe aim of this study was to evaluate the efficacy and safety of the combination of docetaxel (TXT) plus tamoxifen (TAM) in advanced non-small-cell lung cancer (NSCLC) patients who had received platinum-based first-line chemotherapy. A total of 120 advanced NSCLC patients pretreated with platinum-based chemotherapy were randomized into two treatment groups (the TXT and TXT+TAM groups) in a 1 : 1 ratio. Reversal of P-glycoprotein (P-gp) expression, tumor response, progression-free survival, overall survival, and safety were evaluated on an intention-to-treat basis. The median number of cycles of allocated chemotherapy was four in each treatment group (range: 2-6 cycles). The overall response rate and disease control rate in the TXT+TAM group were significantly higher than those in the TXT group (36.7 vs. 15.0% for overall response rate, P=0.007; 85.0 vs. 68.3% for disease control rate, P=0.031). The combination of TXT and TAM could effectively reverse P-gp expression in tumor tissues and provide a significant survival benefit for advanced NSCLC patients compared with TXT alone (11.6 vs. 9.1 months, P=0.030). In addition, in the TXT+TAM group, patients achieving P-gp reversal had a significantly greater median progression-free survival and overall survival than nonreversal patients. Furthermore, the combined therapy showed a safety profile comparable to that of TXT. The combination of TXT and TAM may be an effective and safe treatment option for advanced NSCLC patients who have already developed P-gp-mediated multidrug resistance.
在这个试验里，他莫昔芬的用法是 “80 mg orally three times daily 3 days before TXT chemotherapy and continued for 7 days.” 这样的间歇性的超大剂量用法。
5 M& X. b3 S  V( d& z4 R4 t9 A9 R) ]这样的间歇性的超大剂量用法毒副作用在可接受范围内：“There were no drug-related ADRs of grade 4 or higher in either treatment group.”“However, these ADRs were mild (grades 1 and 2) and did not require any medical intervention or discontinuation of treatment.”
  T5 u! ]9 K8 w5 L' |  ]1 x7 x8 G2 |但是要注意他莫昔芬对女性患者特有的子宫内膜增厚的副作用。用他莫昔芬应该同时装个曼月乐避孕装置来减缓子宫内膜增厚的副作用。

2、正常说明书剂量的阿帕替尼起到p-gp抑制作用，增加肿瘤内紫杉醇药物的浓度
（1）《Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters》
4 p" Q! E7 s; d' pTo ascertain the potential mechanism by which apatinib sensitizes the MDR cells to antineoplastic drugs, we examined the effect of apatinib on the accumulation of DOX and Rho 123 in cells overexpressing ABCB1 or ABCG2. In the absence of apatinib, the intracellular levels of DOX and Rho 123 were low in MDR cells, whereas apatinib significantly increased the intracellular accumulation of DOX and Rho 123 in a concentration-dependent manner (Fig. 1, Fig. S2, S3). The fluorescence index of DOX, in the presence of 0.75, 1.5 and 3 µM of apatinib, was increased by 1.21-, 1.72- and 2.19-fold, respectively, in KBv200 cells, 1.31-, 1.86- and 2.44-fold, respectively, in MCF-7/adr cells and 1.37-, 1.71-, and 2.11-fold, respectively, in S1-M1-80 cells (Fig. 1A). As shown in Fig. 1B, apatinib, at 0.75, 1.50 and 3 µM, increased the intracellular accumulation of Rho 123 by 1.91-, 3.43- and 5.17-fold, respectively, in KBv200 cells, 1.92-, 2.83- and 3.59-fold, respectively, in MCF-7/adr cells and 2.13-, 3.42-, and 4.16-fold, respectively, in S1-M1-80 cells. However, apatinib did not significantly alter the intracellular accumulation of DOX and Rho 123 in the parental sensitive KB, MCF-7 and S1 cells. It should be noted that S1-M1-80, but not the wild type ABCG2, overexpress the R482G variant, which can transport Rho 123 (36). Taken together, these results suggest that apatinib significantly inhibits ABCB1- and ABCG2-mediated transport in MDR cells.
/ v& X' s" T, i* l3 t（2）《Combined treatment with apatinib and docetaxel in A549 xenograft mice and its cellular pharmacokinetic basis》
6 w3 Y6 i4 I' w0 gApatinib, a small-molecule inhibitor of VEGFR-2, has attracted much attention due to its encouraging anticancer activity in third-line clinical treatment for many malignancies, including non-small cell lung cancer (NSCLC). Its usage in second-line therapy with chemotherapeutic drugs is still under exploration. In this study we investigated the antitumor effect of apatinib combined with docetaxel against NSCLC and its cellular pharmacokinetic basis. A549 xenograft nude mice were treated with apatinib (100 mg/kg every day for 20 days) combined with docetaxel (8 mg/kg, ip, every four days for 5 times). Apatinib significantly enhanced the antitumor effect of docetaxel and alleviated docetaxel-induced liver damage as well as decreased serum transaminases (ALT and AST). LC-MS/MS analysis revealed that apatinib treatment significantly increased the docetaxel concentration in tumors (up to 1.77 times) without enhancing the docetaxel concentration in the serum, heart, liver, lung and kidney. Furthermore, apatinib decreased docetaxel-induced upregulation of P-glycoprotein in tumors. The effects of apatinib on the uptake, efflux and subcellular distribution of docetaxel were investigated in A549 and A549/DTX (docetaxel-resistant) cells in vitro. A cellular pharmacokinetic study revealed that apatinib significantly increased cellular/subcellular accumulation (especially in the cytosol) and decreased the efflux of docetaxel in A549/DTX cells through P-gp, while apatinib exerted no significant effect on the cellular pharmacokinetics of docetaxel in A549 cells. Consequently, the IC50 value of docetaxel in A549/DTX cells was more significantly decreased by apatinib than that in A549 cells. These results demonstrate that apatinib has potential for application in second-line therapy combined with docetaxel for NSCLC patients, especially for docetaxel-resistant or multidrug-resistant patients.
这篇论文里阿帕替尼的小鼠剂量是 with apatinib (100 mg/kg every day for 20 days) ，这个剂量换算成人体剂量在 11毫克每公斤，一个60公斤的患者每天用660毫克。而阿帕替尼的说明书 剂量 是 “推荐剂量：850mg，每日1次。”
9 q! @- T1 w: T5 [7 ]  p说明这个把阿帕替尼当p-gp抑制剂用的剂量还在说明书正常剂量范围内，可行性比较大。

四、Relacorilant 拮抗 glucocorticoid receptor，抑制CYP3A4，延缓白紫耐药
6 N# d- v! x/ l5 F0 L4 CRelacorilant (CORT125134)是一种有效的、选择性和口服生物可利用的糖皮质激素受体（glucocorticoid receptor）拮抗剂。CAS号：1496510-51-0。分子量：586.56。Relacorilant也是是一种强效的CYP3A4抑制剂。
6 h- d4 J; S/ F6 b& I; w: D) S( o《Relacorilant + Nab-Paclitaxel in Patients With Recurrent, Platinum-Resistant Ovarian Cancer: A Three-Arm, Randomized, Controlled, Open-Label Phase II Study》
1 p2 r" r: g- C* `; Z+ L5 VMethods: This three-arm, randomized, controlled, open-label phase II study (ClinicalTrials.gov identifier: NCT03776812) enrolled women with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer, or ovarian carcinosarcoma treated with ≤4 prior chemotherapeutic regimens. Patients were randomly assigned 1:1:1 to (1) nab-paclitaxel (80 mg/m2) + intermittent relacorilant (150 mg the day before, of, and after nab-paclitaxel); (2) nab-paclitaxel (80 mg/m2) + continuous relacorilant (100 mg once daily); or (3) nab-paclitaxel monotherapy (100 mg/m2). Nab-paclitaxel was administered on days 1, 8, and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) by investigator assessment; objective response rate (ORR), duration of response (DOR), overall survival (OS), and safety were secondary end points.
Results: A total of 178 women were randomly assigned. Intermittent relacorilant + nab-paclitaxel improved PFS (hazard ratio [HR], 0.66; log-rank test P = .038; median follow-up, 11.1 months) and DOR (HR, 0.36; P = .006) versus nab-paclitaxel monotherapy, while ORR was similar across arms. At the preplanned OS analysis (median follow-up, 22.5 months), the OS HR was 0.67 (P = .066) for the intermittent arm versus nab-paclitaxel monotherapy. Continuous relacorilant + nab-paclitaxel showed numerically improved median PFS but did not result in significant improvement over nab-paclitaxel monotherapy. Adverse events were comparable across study arms, with neutropenia, anemia, peripheral neuropathy, and fatigue/asthenia being the most common grade ≥3 adverse events.
Conclusion: Intermittent relacorilant + nab-paclitaxel improved PFS, DOR, and OS compared with nab-paclitaxel monotherapy. On the basis of protocol-prespecified Hochberg step-up multiplicity adjustment, the primary end point did not reach statistical significance (P < .025). A phase III evaluation of this regimen is underway (ClinicalTrials.gov identifier: NCT05257408).
( D) d1 J$ }& L- Y( _3 I7 {% [
( C* y! `9 u; L  P7 G- d+ w$ f7 B五、同时抑制ERα 可增强白紫对 ER+ 乳腺癌的疗效
《Estrogen receptor α inhibits Caveolin 1 translation by promoting m6A-dependent miR199a-5p maturation to confer nab-paclitaxel resistance》
Estrogen receptor positive (ER+) breast cancer patients exhibit poorer responsiveness to nab-paclitaxel compared to ER negative (ER-) patients, with the underlying mechanisms remaining unknown. Caveolin 1 (CAV1) is a membrane invagination protein critical for the endocytosis of macromolecules including albumin-bound chemotherapeutic agents. Here, we demonstrate that ERα limits the efficacy of nab-paclitaxel in breast cancer cells while genetic or pharmacological inhibition of ERα increased the sensitivity of ER+ breast cancer cells to nab-paclitaxel. Notably, CAV1 expression inversely correlates with ERα and relates to improved clinical outcomes from nab-paclitaxel treatment. Importantly, ERα stimulates m6A dependent maturation of miR199a-5p, which is elevated in ER+ breast cancer, to inhibit CAV1 translation by antagonizing m6A modification of CAV1 mRNA. Together, our findings reveal a novel role of ERα in promoting m6A modification and subsequent maturation of miR199a-5p, which is upregulated in ER+ breast cancer, leading to the suppression of m6A modification of CAV1 and its mRNA translation, thereby contributing to nab-paclitaxel resistance. Thus, combining an ER antagonist with nab-paclitaxel could offer a promising strategy for treating ER+ breast cancer patients.
9 P. g* a% x8 o' u0 Y抑制 ERα的有他莫昔芬、氟维司群、巴多昔芬、拉索昔芬、西黄丸等药物。
% Z( q8 B) j) [0 f8 g
5 F7 g- D5 L, v# @六、西黄丸
6 O* I8 r5 N6 \6 j4 x《西黄胶囊联合白蛋白紫杉醇治疗晚期三阴性乳腺癌临床研究》
( B9 |% c! c6 ?* v! W" j4 A+ q选择于本院就诊的80例晚期三阴性乳腺癌患者作为研究对象。所有患者随机分为对照组和治疗组,每组40例。对照组iv给予白蛋白紫杉醇,21d为1个疗程,治疗3个疗程;治疗组在对照组治疗方案的基础上给予6粒/次的西黄胶囊,每日2次,21 d为一个疗程,治疗3个疗程。
1 v. b+ H, {( ~两组患者治疗后,客观缓解率(ORR)对照组为60.0%,治疗组为75.0%;疾病控制率(CBR)对照组为77.5%,治疗组为87.5%,两组差异显著(P<0.05)。
. D6 X% [& r* T- d4 y治疗组不良反应发生率与对照组比较显著降低(P<0.05)。
# L% b2 _; e5 m5 U  a( g
七、艾迪注射液
《艾迪注射液联合注射液紫杉醇（白蛋白结合型）治疗中晚期肺癌的临床疗效观察》
) O2 e3 N8 y( K收治肺癌患者78例,随机分为对照组38例和研究组40例。对照组基于注射液紫杉醇(白蛋白结合型)方案治疗,研究组在此基础上联合艾迪注射液治疗。
研究组患者近期总有效率为65％(26/40)，明显高于对照组的52.63％(20/38)，两组有统计学差异(P＜0.05)。
研究组患者骨髓抑制、胃肠道反应发生率分别为23(57.50%）、11(27.5%)，显著低于对照组的27(71.05%)、15(39.47%)（P＜0.05）。
, J* Z% e0 B* g2 ^- n
) T& f2 m. j9 ~4 k/ ?* g八、厄贝沙坦
《Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis》
Results: High-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy.
9 @2 c7 d, l3 U  Y: @1 P
' m. N) T: R: ]7 J0 P' z; w6 h九、抑制BCL-2
《Low Bcl-2 is a robust biomarker of sensitivity to nab-paclitaxel in Ewing sarcoma》
" }2 e4 v' p+ d) O7 zhe negative correlation of Bcl-2 immunoblotting signal and activity was especially robust (r = 0.8352; P = 0.0007; Pearson correlation). Consequently, we evaluated pharmacological strategies to inhibit Bcl-2 during nab-paclitaxel treatment. We observed that the Bcl-2 inhibitor venetoclax improved the activity of nab-paclitaxel in highly resistant Bcl-2-expressing Ewing sarcoma PDX. Overall, our results suggest that low Bcl-2 expression could be used to select patients with Ewing sarcoma sensitive to nab-paclitaxel, and Bcl-2 inhibitors could improve the activity of this drug in Bcl-2-expressing Ewing sarcoma.
) W8 J5 `: V$ Q* Y# g6 g$ j9 lBcl-2抑制剂有venetoclax等药物。

) {! k/ [* s/ y十、匹莫齐特
3 v2 n& r6 ?4 y. h8 G5 `1、《Molecular-level effects of eribulin and paclitaxel on breast cancer based on differential co-expression network analysis》
( k6 e, J8 z( X1 L0 R4 e8 |3 IWe investigated the effects of eribulin and paclitaxel on breast cancer (BC) by exploring molecular biomarkers and pathways. Co-expression networks were constructed by differentially co-expressed genes and links, and centralities were analyzed to explore the hub genes. Pathway-enrichment analysis was performed. The hub genes were validated using the polymerase chain reaction and western blotting. A total of 132 and 153 differentially expressed genes were identified in BC cell lines treated with eribulin and paclitaxel, respectively. Six hub genes were identified in two co-expression networks. The spliceosome pathway was the mutually significant pathway. The validation analysis was basically consistent with the bioinformatics. We successfully identified several hub genes and pathways relevant to the effects of eribulin and paclitaxel on BC based on the network analysis.
, w  ~$ y) B6 i( P# p其中紫杉烷组阈值最高的枢纽基因是KIF20A 。

# A& C! a; j4 R1 t* U2、KIF20A 过表达是 紫杉烷耐药的重要原因之一。
（1）《Paclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel resistance》
The physiological relevance of the regulation of KIF20A by FOXM1 is further highlighted by the strong and significant correlations between FOXM1 and KIF20A expression in breast cancer patient samples. Statistical analysis reveals that both FOXM1 and KIF20A protein and mRNA expression significantly associates with poor survival, consistent with a role of FOXM1 and KIF20A in paclitaxel action and resistance. Collectively, our findings suggest that paclitaxel targets the FOXM1-KIF20A axis to drive abnormal mitotic spindle formation and mitotic catastrophe and that deregulated FOXM1 and KIF20A expression may confer paclitaxel resistance.
" R) k$ b0 C3 @  W" s. \& f（2）《A Network of 17 Microtubule-Related Genes Highlights Functional Deregulations in Breast Cancer》
A wide panel of microtubule-associated proteins and kinases is involved in coordinated regulation of the microtubule cytoskeleton and may thus represent valuable molecular markers contributing to major cellular pathways deregulated in cancer. We previously identified a panel of 17 microtubule-related (MT-Rel) genes that are differentially expressed in breast tumors showing resistance to taxane-based chemotherapy. In the present study, we evaluated the expression, prognostic value and functional impact of these genes in breast cancer. We show that 14 MT-Rel genes (KIF4A, ASPM, KIF20A, KIF14, TPX2, KIF18B, KIFC1, AURKB, KIF2C, GTSE1, KIF15, KIF11, RACGAP1, STMN1) are up-regulated in breast tumors compared with adjacent normal tissue. Six of them (KIF4A, ASPM, KIF20A, KIF14, TPX2, KIF18B) are overexpressed by more than 10-fold in tumor samples and four of them (KIF11, AURKB, TPX2 and KIFC1) are essential for cell survival. Overexpression of all 14 genes, and underexpression of 3 other MT-Rel genes (MAST4, MAPT and MTUS1) are associated with poor breast cancer patient survival. A Systems Biology approach highlighted three major functional networks connecting the 17 MT-Rel genes and their partners, which are centered on spindle assembly, chromosome segregation and cytokinesis. Our studies identified mitotic Aurora kinases and their substrates as major targets for therapeutic approaches against breast cancer.
/ \3 C% ?7 w; m" [
( V+ m. r2 b! z) i1 b5 E6 s' I( z3、AURKB的失调也是紫杉烷耐药的重要原因之一
/ g, ?: C" r8 n（1） 《Role of aurora kinase B in regulating resistance to paclitaxel in breast cancer cells》
Aurora kinase B (AURKB) is a type of functional kinase with primary functions of participating in cell mitosis, which has been identified to be involved in the occurrence and development of malignant tumors strongly. However, it still remains a controversial with respect to the relationship between the phosphorylation level of AURKB and its function. In our initial research, there was no significant difference in the relative content of AURKB protein between drug-resistant breast cancer cells and wild-type cells; however, its phosphorylation level in drug-resistant cells was significantly higher than that in wild-type cells. Subsequent cell and animal experiments both confirmed the positive correlation between AURKB phosphorylation and drug resistance. Furthermore, PRKCE in the upstream was identified to regulate the phosphorylation of AURKB, which promoted the change of spatial localization of AURKB from nucleus to cytoplasm. Accordingly, phosphorylated AURKB reduced the negative regulation of downstream RAB27B transcription physically, and interacted with RAB27B in cytoplasm to maintain its protein stability. Eventually, it promoted exosome secretion of drug-resistant cells and drug efflux. Using shRNA to knockdown AURKB expression, using hesperadin to inhibit AURKB activity, mutating the AURKB phosphorylation site, or using siRNA as well as BIM to inhibit the activity of the upstream AURKB phosphorylation regulatory protein PRKCE, all of which directly or indirectly reduce AURKB phosphorylation, are effective in reversing PTX resistance in cells. Collectively, this study provides experimental evidence for PRKCE/AURKB/RAB27B axis in regulating the resistance to paclitaxel (PTX) in breast cancer cells, offering a potential intervention target for reversing drug resistance.
（2） 《Aurora B expression modulates paclitaxel response in non-small cell lung cancer》
8 S! i! D9 ]& z7 z% t3 GResults: Frequent AURKB mRNA upregulation was observed in NSCLC tissues (P<0.0001), being more prominent in squamous carcinomas (P<0.0001). Aurora B expression in cell lines strongly correlated with sensitivity to both docetaxel (P=0.004) and paclitaxel (P=0.007). Aurora B knockdown derivatives consistently showed a dose-dependent association between low-AURKB expression and resistance to paclitaxel. Specific chemical inhibition of Aurora B activity also demonstrated a strong dose-dependent efficiency in triggering paclitaxel resistance.
! r4 W$ p7 Z5 L3 m5 o6 M0 k3 K3 j/ w: N
2 Y+ L. ~; J$ m8 u: J4、匹莫齐特抑制 KIF20A 和 AURKB，延缓紫杉烷药物的耐药
% }; ]: F2 n" v《Discovery of a new candidate drug to overcome cabazitaxel-resistant gene signature in castration-resistant prostate cancer by in silico screening》
Results: We identified pimozide as a promising candidate drug for CBZ-resistant CRPC. Pimozide had a significant antitumor effect on DU145CR cells. Moreover, combination treatment with pimozide and CBZ had a synergic effect for DU145CR cells in vitro and in vivo. Microarray analysis identified AURKB and KIF20A as potential targets of pimozide in CBZ-resistant CRPC. DU145CR had significantly higher AURKB and KIF20A expression compared with a non-CBZ-resistant cell line. Inhibition of AURKB and KIF20A had an antitumor effect in DU145CR xenograft tumors. Higher expression of AURKB and KIF20A was a poor prognostic factor of TGCA prostate cancer cohort. CBZ-resistant prostate cancer tissues in our institution had higher AURKB and KIF20A expression.
4 i: {) z( ~2 P) z