伊马替尼治疗胃肠道间质瘤的继发性耐药机制

甲磺酸伊马替尼是一种高效的酪氨酸激酶抑制剂,在临床上用于进展期或手术不能切除胃肠道间质瘤(GIST)的患者.虽然取得了很好的疗效,但是容易产生耐药,耐药机制主要有原发性耐药和继发性耐药,其中继发性耐药成为近些年研究的焦点.通过对继发性耐药机制的研究,可探讨新的治疗策略.     

酪氨酸激酶抑制剂耐药的分子机制及耐药后治疗策略

酪氨酸激酶抑制剂(TKI)治疗慢性粒细胞性白血病(CML)的效果虽然显著,但治疗过程中产生的耐药问题仍无法避免.因此,TKI耐药是CML治疗失败的主要原因之一.据报道,约5%的患者对TKI存在原发性耐药,20%~30%的患者对TKI产生继发性耐药.目前已知的TKI耐药分子机制有bcr-abl过表达、基因突变、DNA修复机制缺陷、ATP-binding cassette(ABC)转运蛋白介导的药物外排、异常信号通路及骨髓微环境等.同时,针对各种耐药机制开发的药物多处于临床前或临床研究阶段,这些药物的研究为克服TKI耐药提供了可能.本文拟对TKI耐药的分子机制及耐药后治疗策略的进展进行综述.     

ER通路信号传导与选择性雌激素受体调节剂耐药机制研究

内分泌治疗是乳腺癌综合治疗中的重要措施之一,此疗法面临的最大难题是原发性、继发性耐药,其确切机制尚不清楚.雌激素受体(ER)信号传导途径及各辅助因子的分子调控是近年来研究的重点,现综述有关研究进展,以期为临床选择性ER调节剂(SERM)耐药病例的治疗及耐药逆转提供帮助.     

肿瘤多药耐药的研究进展

肿瘤细胞对化学治疗药物产生耐药性是肿瘤治疗不能取得治愈性疗效的重要原因之一.这种耐药性可以在开始化疗时即存在,称为原发性或内在性耐药,也可发生于化疗进行的过程中,称为继发性或获得性耐药.长期以来,对肿瘤的耐药机制进行了不少研究,并在用药的方案、方式、方法上作了大量观察,但结果都不甚满意.     

肿瘤多药耐药机制的研究进展

肿瘤多药耐药性（multidrug resistance ,MDR） 是指肿瘤细胞在接触一种抗肿瘤药产生耐药性后,对未接触过的、结构不同、作用机制各异的其他抗肿瘤药物也具有交叉耐药性.MDR有两种表型： 一种是首次使用化疗药物就产生耐药,称为原发性耐药（Primary resistance） 或天然性耐药（Initialresistance）;另一种则是在化疗过程中产生耐药,称为继发性耐药（Secondary resistance） 或获得性耐药（Acquiredresistance）.目前化疗是恶性肿瘤治疗中除手术、放疗以外最重要的手段,然而许多肿瘤常规化疗效果差,甚至失败.近年来研究表明肿瘤MDR已成为肿瘤成功化疗的重要障碍之一.因此克服MDR 就成为肿瘤成功化疗的当务之急.但MDR产生机制复杂,是多因素作用的结果.自1970 年Bielder 和Riehm发现MDR现象以来,国内外对其机制进行了广泛的研究.本文就近年来MDR 机制的研究进展做一综述.     

EGFR-TKI治疗非小细胞肺癌的耐药机制进展研究

肺癌的发病率和死亡率已居我国恶性肿瘤的第一位。以表皮生长因子受体,酪氨酸激酶为靶点的酪氨酸激酶抑制剂(EGFR-TKI)治疗肺癌已广泛引起关注。但部分患者在服用EGFR-TKI初期即出现原发耐药,有些患者在服用EGFR-TKI一段时间后产生继发性耐药,本文综述EGFR-TKl分子耐药机制的研究现状,探讨EGFR-TKl分子耐药机制重要的临床意义。      

酪氨酸激酶抑制剂在非小细胞肺癌中的耐药机制

EGFR-TKIs在EGFR突变型非小细胞肺癌治疗中是非常有效的。然而在非小细胞肺癌EGFR突变患者中约有20%天然耐药,即使治疗有效,在10~16月左右会产生继发耐药。迄今为止,研究发现可能的继发性耐药机制包括EGFR二次突变、旁路激活、下游信号激活、小细胞转化及上皮-间质转化（EMT）等。近期,有研究发现BIM基因与TKI耐药相关。本文就有关耐药机制的近期研究进展作一综述。     

乳腺癌内分泌治疗耐药相关信号通路的研究进展

内分泌治疗在乳腺癌综合治疗中占有重要的地位,但原发性与继发性耐药是当前内分泌治疗面临的难题.研究证明,雌激素受体通路与各种因子信号通路的交叉效应是导致乳腺癌内分泌耐药的主要机制之一,针对各种通路的靶向治疗药物也成为了热点.许多临床试验结果表明靶向阻断这些信号通路的药物联合内分泌治疗药物可显著提高患者的生存率.本文根据PubMed检索获取相关资料,就近年来与乳腺癌内分泌耐药相关的信号通路及治疗策略研究进展进行综述.     

EGFR单克隆抗体治疗转移性结直肠癌的耐药分子机制

靶向表皮生长因子受体（EGFR）的单克隆抗体是转移性结直肠癌（mCRC）的重要治疗药物,但有效率并不理想,主要原因是存在严重的原发性和继发性耐药。本文从分子改变的方面就靶向EGFR单克隆抗体（anti EGFR mAb）治疗mCRC的耐药分子机制作一综述,旨在为进一步研究anti EGFR mAb耐药机制提供参考,为mCRC患者实现临床个体化治疗提供理论依据。     

抗PD-1/PD-L1药物治疗肿瘤耐药机制研究进展

PD-1/PD-L1通路可通过多种机制产生免疫抑制作用,介导肿瘤免疫逃逸.目前针对PD-1/PD-L1通路的研究已成为近几年的热点.区别于传统的化疗及放疗,抗PD-1/抗PD-L1药物介导的免疫靶向治疗,能更加有效地调动机体本身的抗肿瘤免疫能力,改善免疫微环境,在肺癌、黑色素瘤、胃癌等恶性肿瘤治疗中取得了显著效果.但目前抗PD-1/抗PD-L1药物治疗并非所有患者均能获益,部分患者存在原发性耐药,有的患者出现继发性耐药.本文就抗PD-1/PD-L1药物治疗的耐药机制作一综述.     

Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation.

Most gastrointestinal stromal tumors (GIST) have an activating mutation in either KIT or PDGFRA. Imatinib is a selective tyrosine kinase inhibitor and achieves a partial response or stable disease in about 80% of patients with metastatic GIST. It is now clear that some patients with GIST develop resistance to imatinib during chronic therapy. To identify the mechanism of resistance, we studied 31 patients with GIST who were treated with imatinib and then underwent surgical resection. There were 13 patients who were nonresistant to imatinib, 3 with primary resistance, and 15 with acquired resistance after initial benefit from the drug. There were no secondary mutations in KIT or PDGFRA in the nonresistant or primary resistance groups. In contrast, secondary mutations were found in 7 of 15 (46%) patients with acquired resistance, each of whom had a primary mutation in KIT exon 11. Most secondary mutations were located in KIT exon 17. KIT phosphorylation was heterogeneous and did not correlate with clinical response to imatinib or mutation status. That acquired resistance to imatinib in GIST commonly occurs via secondary gene mutation in the KIT kinase domain has implications for strategies to delay or prevent imatinib resistance and to employ newer targeted therapies.     

Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance

Although ovarian carcinomas with mutated BRCA1 or BRCA2 are sensitive to platinum compounds, such carcinomas eventually develop platinum resistance. Previously, we showed that acquired resistance to cisplatin in BRCA2-mutated tumors can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. Here, we show that secondary mutations of BRCA1 also occur in BRCA1-mutated ovarian cancer with platinum resistance. We evaluated nine recurrent BRCA1-mutated ovarian cancers previously treated with platinum compounds, including five with acquired platinum resistance, one with primary platinum resistance, and three with platinum sensitivity. Four of the six recurrent platinum-resistant tumors had developed secondary genetic changes in BRCA1 that restored the reading frame of the BRCA1 protein, whereas none of the three platinum-sensitive recurrent tumors developed BRCA1 sequence alterations. We immunohistochemically confirmed restored expression of BRCA1 protein in two cases with secondary mutations. Intriguingly, the case with primary platinum resistance showed back mutation of BRCA1 in the primary tumor and showed another secondary mutation in the recurrent tumor. Our results suggest that secondary mutations in BRCA1 can mediate resistance to platinum in BRCA1-mutated ovarian tumors.     

Efficacy of docetaxel 60 mg/m2 in patients with metastatic breast cancer according to the status of anthracycline resistance.

PURPOSE: To evaluate the efficacy of docetaxel 60 mg/m2 in metastatic breast cancer (MBC) according to the status of anthracycline resistance. PATIENTS AND METHODS: Ninety-nine patients with anthracycline-resistant MBC were treated with docetaxel 60 mg/m2 intravenously for a 90-minute period every 3 to 4 weeks. Anthracycline resistance was defined as primary and secondary resistance. Primary resistance was defined as progression during or within 6 months after completion of adjuvant anthracycline, and no MBC response to a first-line regimen that contained anthracycline. Secondary resistance was defined as progression after a documented clinical response to a first-line anthracycline treatment for MBC. Secondary resistance was further divided into three categories: (1) absolute resistance, or progression during treatment with anthracycline after a period of response; (2) relative resistance, or progression within 6 months after anthracycline administration ended; and (3) sensitive regrowth, or progression more than 6 months after the conclusion of anthracycline administration. RESULTS: The response rate in the 99 patients was 35.4% (95% confidence interval, 30.1% to 44.8%). The response rates according to the status of anthracycline resistance were as follows: primary resistance (n = 46), 19.6%; secondary resistance (n = 53), 49.1% (absolute resistance [n = 16], 56.3%); relative resistance (n = 17), 47.1%; and sensitive regrowth (n = 20), 45.0%. The median time to treatment failure in patients with primary resistance was 2.9 months, compared with 5.2 months in patients with secondary resistance (P = .0022). CONCLUSION: Docetaxel at a dose of 60 mg/m2 seemed to be effective in MBC with secondary resistance to anthracycline. The status of anthracycline resistance is important for the prediction of response to second-line treatment with docetaxel.     

Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors

Most gastrointestinal stromal tumors (GISTs) are associated with activating kinase mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene, and imatinib has revolutionized the care of advanced GISTs. However, most patients gradually developed resistance to imatinib. We intend to identify the secondary kinase mutations in imatinib-resistant GISTs and to study the relationship between secondary kinase mutations and the clinical response to imatinib. Twelve advanced GIST patients, who have developed resistance to imatinib were included in this study. Paraffin-embedded pretreatment GIST specimens and progression lesions of the tumors after resistance to imatinib were analyzed for kinase mutations in exons 9, 11, 13, and 17 of KIT gene and exons of 10, 12, 14, and 18 of PDGFRA gene. Primary KIT mutations have been found in all but one of the primary tumors including one case harboring de novo double KIT exon 11 mutations. Secondary kinase mutations in KIT and PDGFRA were found in seven and 1 of 12 patients, respectively. Two patients harbored more than one secondary KIT mutations in different progression sites, and there are four types of clonal or polyclonal evolution being observed. The secondary PDGFRA exon 14 mutation H687Y is a novel mutation that has never been reported before. Acquired secondary kinase mutations are the most important cause of secondary imatinib resistance in advanced GISTs. The identification of secondary kinase mutations is important in the development of new therapeutic strategies.     

表皮生长因子受体-酪氨酸激酶抑制剂的耐药机制

表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKI）在非小细胞肺癌（NSCLC）中的耐药越来越常见,主要包括原发性耐药与继发性耐药,其中原发性耐药主要与EGFR基因突变有关,继发性耐主要与T790M、MET等基因相关。     

吉非替尼在非小细胞肺癌治疗中的继发耐药

吉非替尼是一种表皮生长因子受体(EGFR)酪氨酸激酶抑制剂,对非小细胞肺癌(NSCLC)有良好的抗肿瘤活性,但大多数患者最终因继发耐药出现病情进展.在发生EGFR基因突变的肺腺癌患者中,约半数吉非替尼继发耐药与二次突变有关,这种二次突变导致EGFR 790位上的苏氨酸被甲硫氨酸所取代(T790M).其他导致耐药的机制包括EGFR受体的内化现象以及MET基因扩增.     

KRAS Secondary Mutations That Confer Acquired Resistance to KRAS G12C Inhibitors,Sotorasib and Adagrasib,and Overcoming Strategies: Insights From In Vitro Experiments

IntroductionKRAS mutations have been recognized as undruggable for many years. Recently, novel KRAS G12C inhibitors, such as sotorasib and adagrasib, are being developed in clinical trials and have revealed promising results in metastatic NSCLC. Nevertheless, it is strongly anticipated that acquired resistance will limit their clinical use. In this study, we developed in vitro models of the KRAS G12C cancer, derived from resistant clones against sotorasib and adagrasib, and searched for secondary KRAS mutations as on-target resistance mechanisms to develop possible strategies to overcome such resistance.MethodsWe chronically exposed Ba/F3 cells transduced with KRAS^G12C to sotorasib or adagrasib in the presence of N-ethyl-N-nitrosourea and searched for secondary KRAS mutations. Strategies to overcome resistance were also investigated.ResultsWe generated 142 Ba/F3 clones resistant to either sotorasib or adagrasib, of which 124 (87%) harbored secondary KRAS mutations. There were 12 different secondary KRAS mutations. Y96D and Y96S were resistant to both inhibitors. A combination of novel SOS1 inhibitor, BI-3406, and trametinib had potent activity against this resistance. Although G13D, R68M, A59S and A59T, which were highly resistant to sotorasib, remained sensitive to adagrasib, Q99L was resistant to adagrasib but sensitive to sotorasib.ConclusionsWe identified many secondary KRAS mutations causing resistance to sotorasib, adagrasib, or both, in vitro. The differential activities of these two inhibitors depending on the secondary mutations suggest sequential use in some cases. In addition, switching to BI-3406 plus trametinib might be a useful strategy to overcome acquired resistance owing to the secondary Y96D and Y96S mutations.     

Evolution of platinum resistance in high-grade serous ovarian cancer

High-grade serous ovarian cancers account for most ovarian-cancer mortality. Although this disease initially responds well to platinum-based chemotherapy, relapse and progression to chemotherapy resistance are frequently seen. Time to relapse after first-line therapy is a predictor of response to secondary platinum treatment: more than 12 months is associated with high chance of a secondary response, whereas relapses within 6 months generally indicate platinum resistance. In this Personal View we discuss whether patterns of response, relapse, and the development of drug resistance in high-grade serous ovarian cancers are related to distinct underlying molecular and cellular biological characteristics. In particular, we propose that rapid relapse with platinum-resistant disease is due to minor subpopulations of intrinsically resistant cancer cells at presentation.     

Molecular basis for primary and secondary tyrosine kinase inhibitor resistance in gastrointestinal stromal tumor

Small molecule kinase inhibitors have irrevocably altered cancer treatment. March 2010 marks the 10th anniversary of using imatinib in gastrointestinal stromal tumors (GIST), a cardinal example of the utility of such targeted therapy in a solid tumor. Before imatinib, metastatic GIST was frustrating to treat due to its resistance to standard cytotoxic chemotherapy. Median survival for patients with metastatic GIST improved from 19 to 60?months with imatinib. In treating patients with GIST, two patterns of tyrosine kinase inhibitor resistance have been observed. In the first, ~9-14% of patients have progression within 3?months of starting imatinib. These patients are classified as having primary or early resistance. Median progression-free survival (PFS) on imatinib is approximately 24?months; patients with later progression are classified as having secondary or acquired resistance. Primary studies and a meta-analysis of studies of imatinib in GIST patients have identified prognostic features that contribute to treatment failure. One of the strongest predictors for success of therapy is KIT or PDGFRA mutational status. Patients with KIT exon 11 mutant GIST have better response rates, PFS, and overall survival compared to other mutations. A great deal has been learned in the last decade about sensitivity and resistance of GIST to imatinib; however, many unanswered questions remain about secondary resistance mechanisms and clinical management in the third- and fourth-line setting. This review will discuss the role of dose effects, and early and late resistance to imatinib and their clinical implications. Patients intolerant to imatinib (5%) and those who progress on imatinib are treated with sunitinib. The mechanism of resistance to sunitinib is unknown at this time but is also appears related to growth of clones with secondary mutations in KIT. Third- and fourth-line treatments of GIST and with future treatment strategies are also discussed.