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The multidrug resistance transporter P-glycoprotein confers resistance to ferroptosis inducers. 多药耐药性转运蛋白P-糖蛋白赋予对脱铁性贫血诱导物的耐药性。
Q1 ONCOLOGY Pub Date : 2023-07-27 eCollection Date: 2023-01-01 DOI: 10.20517/cdr.2023.29
William J E Frye, Lyn M Huff, José M González Dalmasy, Paula Salazar, Rachel M Carter, Ryan T Gensler, Dominic Esposito, Robert W Robey, Suresh V Ambudkar, Michael M Gottesman

Aim: Ferroptosis is a non-apoptotic form of cell death caused by lethal lipid peroxidation. Several small molecule ferroptosis inducers (FINs) have been reported, yet little information is available regarding their interaction with the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp, ABCB1) and ABCG2. We thus sought to characterize the interactions of FINs with P-gp and ABCG2, which may provide information regarding oral bioavailability and brain penetration and predict drug-drug interactions. Methods: Cytotoxicity assays with ferroptosis-sensitive A673 cells transfected to express P-gp or ABCG2 were used to determine the ability of the transporters to confer resistance to FINs; confirmatory studies were performed in OVCAR8 and NCI/ADR-RES cells. The ability of FINs to inhibit P-gp or ABCG2 was determined using the fluorescent substrates rhodamine 123 or purpuin-18, respectively. Results: P-gp overexpression conferred resistance to FIN56 and the erastin derivatives imidazole ketone erastin and piperazine erastin. P-gp-mediated resistance to imidazole ketone erastin and piperazine erastin was also reversed in UO-31 renal cancer cells by CRISPR-mediated knockout of ABCB1. The FINs ML-162, GPX inhibitor 26a, and PACMA31 at 10 µM were able to increase intracellular rhodamine 123 fluorescence over 10-fold in P-gp-expressing MDR-19 cells. GPX inhibitor 26a was able to increase intracellular purpurin-18 fluorescence over 4-fold in ABCG2-expressing R-5 cells. Conclusion: Expression of P-gp may reduce the efficacy of these FINs in cancers that express the transporter and may prevent access to sanctuary sites such as the brain. The ability of some FINs to inhibit P-gp and ABCG2 suggests potential drug-drug interactions.

目的:脱铁性贫血是由致命的脂质过氧化引起的一种非凋亡形式的细胞死亡。已经报道了几种小分子脱铁诱导剂(FINs),但关于它们与ATP结合盒(ABC)转运蛋白P-糖蛋白(P-gp,ABCB1)和ABCG2的相互作用的信息很少。因此,我们试图表征FINs与P-gp和ABCG2的相互作用,这可能提供有关口服生物利用度和脑渗透的信息,并预测药物与药物的相互作用。方法:用转染表达P-gp或ABCG2的脱铁敏感A673细胞进行细胞毒性测定,以确定转运蛋白赋予FINs抗性的能力;在OVCAR8和NCI/ADR-RES细胞中进行了验证性研究。分别使用荧光底物罗丹明123或purpuin-18测定FINs抑制P-gp或ABCG2的能力。结果:P-gp过表达对FIN56和erastin衍生物咪唑酮erastin和哌嗪erastin产生耐药性。通过CRISPR介导的ABCB1敲除,P-gp介导的对咪唑酮erastin和哌嗪erastin的耐药性在UO-31癌症细胞中也被逆转。10µM的FINs ML-162、GPX抑制剂26a和PACMA31能够在P-gp-expressing MDR-19细胞中将细胞内罗丹明123荧光增加10倍以上。GPX抑制剂26a能够在表达ABCG2的R-5细胞中使细胞内嘌呤-18荧光增加4倍以上。结论:P-gp的表达可能会降低这些FINs在表达转运蛋白的癌症中的疗效,并可能阻止进入大脑等保护区。一些FINs抑制P-gp和ABCG2的能力表明了潜在的药物相互作用。
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引用次数: 2
Harnessing the value of TCTP in breast cancer treatment resistance: an opportunity for personalized therapy. 利用TCTP在乳腺癌症治疗耐药性中的价值:个性化治疗的机会。
Q1 ONCOLOGY Pub Date : 2023-07-13 eCollection Date: 2023-01-01 DOI: 10.20517/cdr.2023.21
Gianluca Santamaria, Mario Cioce, Antonia Rizzuto, Vito Michele Fazio, Giuseppe Viglietto, Maria Lucibello

Early identification of breast cancer (BC) patients at a high risk of progression may aid in therapeutic and prognostic aims. This is especially true for metastatic disease, which is responsible for most cancer-related deaths. Growing evidence indicates that the translationally controlled tumor protein (TCTP) may be a clinically relevant marker for identifying poorly differentiated aggressive BC tumors. TCTP is an intriguing protein with pleiotropic functions, which is involved in multiple signaling pathways. TCTP may also be involved in stress response, cell growth and proliferation-related processes, underlying its potential role in the initiation of metastatic growth. Thus, TCTP marks specific cancer cell sub-populations with pronounced stress adaptation, stem-like and immune-evasive properties. Therefore, we have shown that in vivo phospho-TCTP levels correlate with the response of BC cells to anti-HER2 agents. In this review, we discuss the clinical relevance of TCTP for personalized therapy, specific TCTP-targeting strategies, and currently available therapeutic agents. We propose TCTP as an actionable clinically relevant target that could potentially improve patient outcomes.

早期识别进展风险高的癌症(BC)患者可能有助于实现治疗和预后目标。转移性疾病尤其如此,它是大多数癌症相关死亡的原因。越来越多的证据表明,翻译控制的肿瘤蛋白(TCTP)可能是鉴定低分化侵袭性BC肿瘤的临床相关标志物。TCTP是一种有趣的多效性蛋白,参与多种信号通路。TCTP还可能参与应激反应、细胞生长和增殖相关过程,这是其在转移生长起始中潜在作用的基础。因此,TCTP标记具有显著应激适应、干样和免疫逃避特性的特定癌症细胞亚群。因此,我们已经表明,体内磷酸化TCTP水平与BC细胞对抗HER2药物的反应相关。在这篇综述中,我们讨论了TCTP在个性化治疗中的临床相关性、特定的TCTP靶向策略以及目前可用的治疗药物。我们建议TCTP作为一个可操作的临床相关靶点,有可能改善患者的预后。
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引用次数: 0
Statins markedly potentiate aminopeptidase inhibitor activity against (drug-resistant) human acute myeloid leukemia cells. 他汀类药物显著增强氨肽酶抑制剂对(耐药)人类急性髓系白血病细胞的活性。
Q1 ONCOLOGY Pub Date : 2023-07-04 eCollection Date: 2023-01-01 DOI: 10.20517/cdr.2023.20
Gerrit Jansen, Marjon Al, Yehuda G Assaraf, Sarah Kammerer, Johan van Meerloo, Gert J Ossenkoppele, Jacqueline Cloos, Godefridus J Peters

Aim: This study aimed to decipher the molecular mechanism underlying the synergistic effect of inhibitors of the mevalonate-cholesterol pathway (i.e., statins) and aminopeptidase inhibitors (APis) on APi-sensitive and -resistant acute myeloid leukemia (AML) cells. Methods: U937 cells and their sublines with low and high levels of acquired resistance to (6S)-[(R)-2-((S)-Hydroxy-hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3,3 dimethyl-butyric acid cyclopentyl ester (CHR2863), an APi prodrug, served as main AML cell line models. Drug combination effects were assessed with CHR2863 and in vitro non-toxic concentrations of various statins upon cell growth inhibition, cell cycle effects, and apoptosis induction. Mechanistic studies involved analysis of Rheb prenylation required for mTOR activation. Results: A strong synergy of CHR2863 with the statins simvastatin, fluvastatin, lovastatin, and pravastatin was demonstrated in U937 cells and two CHR2863-resistant sublines. This potent synergy between simvastatin and CHR2863 was also observed with a series of other human AML cell lines (e.g., THP1, MV4-11, and KG1), but not with acute lymphocytic leukemia or multiple solid tumor cell lines. This synergistic activity was: (i) specific for APis (e.g., CHR2863 and Bestatin), rather than for other cytotoxic agents; and (ii) corroborated by enhanced induction of apoptosis and cell cycle arrest which increased the sub-G1 fraction. Consistently, statin potentiation of CHR2863 activity was abrogated by co-administration of mevalonate and/or farnesyl pyrophosphate, suggesting the involvement of protein prenylation; this was experimentally confirmed by impaired Rheb prenylation by simvastatin. Conclusion: These novel findings suggest that the combined inhibitory effect of impaired Rheb prenylation and CHR2863-dependent mTOR inhibition instigates a potent synergistic inhibition of statins and APis on human AML cells.

目的:本研究旨在揭示甲羟戊酸胆固醇途径抑制剂(即他汀类药物)和氨肽酶抑制剂(APis)对APi敏感和耐药的急性髓系白血病(AML)细胞协同作用的分子机制。方法:以U937细胞及其对APi前药(6S)-[(R)-2-(S)-羟基氨基甲酰基甲氧基甲基)-4-甲基-戊酰基氨基]-3,3二甲基丁酸环戊基酯(CHR2863)获得性抗性低、高的亚系为主要AML细胞系模型。用CHR2863和体外无毒浓度的各种他汀类药物评估药物组合对细胞生长抑制、细胞周期效应和细胞凋亡诱导的影响。机理研究涉及mTOR激活所需的Rheb异戊二烯化的分析。结果:CHR2863和他汀类药物辛伐他汀、氟伐他汀、洛伐他汀和普伐他汀在U937细胞和两个CHR2863耐药亚系中表现出强烈的协同作用。辛伐他汀和CHR2863之间的这种有效协同作用也在一系列其他人类AML细胞系(例如,THP1、MV4-11和KG1)中观察到,但在急性淋巴细胞白血病或多个实体瘤细胞系中没有观察到。这种协同活性是:(i)对APis(例如,CHR2863和Bestatin)具有特异性,而不是对其他细胞毒性药物具有特异性;和(ii)通过增强的细胞凋亡诱导和细胞周期停滞来证实,其增加了亚G1组分。一致地,他汀类药物对CHR2863活性的增强作用通过甲羟戊酸酯和/或法尼焦磷酸酯的联合给药而被消除,这表明参与了蛋白质的异戊二烯化;辛伐他汀对Rheb异戊二烯化作用的损害在实验上证实了这一点。结论:这些新发现表明,Rheb异戊二烯化受损和CHR2863依赖性mTOR抑制的联合抑制作用促使他汀类药物和APis对人AML细胞产生强大的协同抑制作用。
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引用次数: 0
Review of 5-FU resistance mechanisms in colorectal cancer: clinical significance of attenuated on-target effects. 回顾 5-FU 在结直肠癌中的耐药机制:减弱靶向效应的临床意义。
Q1 ONCOLOGY Pub Date : 2023-04-29 eCollection Date: 2023-01-01 DOI: 10.20517/cdr.2022.136
William H Gmeiner, Charles Chidi Okechukwu

The emergence of chemoresistant disease during chemotherapy with 5-Fluorouracil-based (5-FU-based) regimens is an important factor in the mortality of metastatic CRC (mCRC). The causes of 5-FU resistance are multi-factorial, and besides DNA mismatch repair deficiency (MMR-D), there are no widely accepted criteria for determining which CRC patients are not likely to be responsive to 5-FU-based therapy. Thus, there is a need to systematically understand the mechanistic basis for 5-FU treatment failure and an urgent need to develop new approaches for circumventing the major causes of 5-FU resistance. In this manuscript, we review mechanisms of 5-FU resistance with an emphasis on: (1) altered anabolic metabolism limiting the formation of the primary active metabolite Fluorodeoxyuridylate (5-Fluoro-2'-deoxyuridine-5'-O-monophosphate; FdUMP); (2) elevated expression or activity of the primary enzymatic target thymidylate synthase (TS); and (3) dysregulated programmed cell death as important causes of 5-FU resistance. Importantly, these causes of 5-FU resistance can potentially be overcome through the use of next-generation fluoropyrimidine (FP) polymers (e.g., CF10) that display reduced dependence on anabolic metabolism and more potent TS inhibitory activity.

在以 5-氟尿嘧啶(5-FU)为基础的化疗方案中出现化疗耐药是导致转移性 CRC(mCRC)死亡的一个重要因素。造成 5-FU 耐药的原因是多方面的,除了 DNA 错配修复缺陷(MMR-D)之外,目前还没有公认的标准来确定哪些 CRC 患者可能对以 5-FU 为基础的疗法无效。因此,有必要系统地了解 5-FU 治疗失败的机理基础,并迫切需要开发新的方法来规避 5-FU 耐药的主要原因。在本手稿中,我们回顾了5-FU耐药的机制,重点是(1) 同化代谢改变限制了主要活性代谢产物氟脱氧尿苷酸(5-氟-2'-脱氧尿苷-5'-O-单磷酸;FdUMP)的形成;(2) 主要酶靶胸苷酸合成酶(TS)的表达或活性升高;(3) 细胞程序性死亡失调是5-FU耐药的重要原因。重要的是,通过使用下一代氟嘧啶(FP)聚合物(如 CF10),这些导致 5-FU 耐药的原因有可能被克服,因为这些聚合物对合成代谢的依赖性降低,对 TS 的抑制活性更强。
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引用次数: 0
Targeting MYC-driven lymphoma: lessons learned and future directions. 靶向MYC驱动的淋巴瘤:经验教训和未来方向。
IF 4.6 Q1 ONCOLOGY Pub Date : 2023-04-12 eCollection Date: 2023-01-01 DOI: 10.20517/cdr.2022.127
Sandra Martínez-Martín, Marie-Eve Beaulieu, Laura Soucek

MYC plays a central role in tumorigenesis by orchestrating cell proliferation, growth and survival, among other transformation mechanisms. In particular, MYC has often been associated with lymphomagenesis. In fact, MYC overexpressing lymphomas such as high-grade B-cell lymphoma (HGBL) and double expressor diffuse large B-cell lymphomas (DLBCL), are considered addicted to MYC. In such a context, MYC targeting therapies are of special interest, as MYC withdrawal is expected to result in tumor regression. However, whether high MYC levels are always predictive of increased sensitivity to these approaches is not clear yet. Even though no MYC inhibitor has received regulatory approval to date, substantial efforts have been made to investigate avenues to render MYC a druggable target. Here, we summarize the different classes of molecules currently under development, which mostly target MYC indirectly in aggressive B-cell lymphomas, paying special attention to subtypes with MYC/BCL2 or BCL6 translocations or overexpression.

MYC通过协调细胞增殖、生长和存活等转化机制在肿瘤发生中发挥核心作用。特别是,MYC经常与淋巴肿瘤有关。事实上,MYC过表达淋巴瘤,如高级别B细胞淋巴瘤(HGBL)和双表达弥漫性大B细胞淋巴瘤,被认为对MYC上瘾。在这种情况下,MYC靶向治疗特别令人感兴趣,因为MYC退出有望导致肿瘤消退。然而,高MYC水平是否总是预测对这些方法的敏感性增加,目前尚不清楚。尽管迄今为止还没有MYC抑制剂获得监管部门的批准,但已经做出了大量努力来研究使MYC成为药物靶点的途径。在这里,我们总结了目前正在开发的不同类别的分子,它们主要间接靶向侵袭性B细胞淋巴瘤中的MYC,特别关注MYC/BCL2或BCL6易位或过表达的亚型。
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引用次数: 0
Heterotypic signaling of cancer-associated fibroblasts in shaping the cancer cell drug resistance. 癌症相关成纤维细胞的异型信号形成了癌细胞的抗药性。
IF 4.6 Q1 ONCOLOGY Pub Date : 2023-03-27 eCollection Date: 2023-01-01 DOI: 10.20517/cdr.2022.72
Ramesh Butti, Ashwini Khaladkar, Priya Bhardwaj, Gopinath Prakasam

The context-dependent reciprocal interaction between the cancer cells and surrounding fibroblasts is imperative for regulating malignant potential, metabolic reprogramming, immunosuppression, and ECM deposition. However, recent evidence also suggests that cancer-associated fibroblasts induce chemoresistance in cancer cells to various anticancer regimens. Because of the protumorigenic function of cancer-associated fibroblasts, these stromal cell types have emerged as fascinating therapeutic targets for cancer. However, this notion was recently challenged by studies that targeted cancer-associated fibroblasts and highlighted the underlying heterogeneity by identifying a subset of these cells with tumor-restricting functions. Hence, it is imperative to understand the heterogeneity and heterotypic signaling of cancer-associated fibroblasts to target tumor-promoting signaling processes by sparing tumor-restricting ones. In this review, we discuss the heterogeneity and heterotypic signaling of cancer-associated fibroblasts in shaping drug resistance and also list the cancer-associated fibroblast-targeting therapeutics.

癌细胞与周围成纤维细胞之间的相互影响是调节恶性潜能、代谢重编程、免疫抑制和 ECM 沉积的必要条件。然而,最近的证据也表明,癌症相关成纤维细胞会诱导癌细胞对各种抗癌方案产生化疗抵抗。由于癌症相关成纤维细胞具有原发性致癌功能,这些基质细胞类型已成为令人着迷的癌症治疗靶点。然而,最近一些针对癌症相关成纤维细胞的研究对这一观点提出了挑战,这些研究通过鉴定这些细胞中具有肿瘤抑制功能的亚群,突出了潜在的异质性。因此,当务之急是了解癌症相关成纤维细胞的异质性和异型信号转导,以针对促进肿瘤的信号转导过程,同时避免抑制肿瘤的信号转导过程。在这篇综述中,我们将讨论癌症相关成纤维细胞在形成耐药性方面的异质性和异型信号转导,并列举癌症相关成纤维细胞靶向疗法。
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引用次数: 0
Targeting regulated cell death pathways in acute myeloid leukemia. 以急性髓性白血病中受调控的细胞死亡途径为靶点。
Q1 ONCOLOGY Pub Date : 2023-03-15 eCollection Date: 2023-01-01 DOI: 10.20517/cdr.2022.108
Sylvain Garciaz, Thomas Miller, Yves Collette, Norbert Vey

The use of the BCL2 inhibitor venetoclax has transformed the management of patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. By triggering intrinsic apoptosis, the drug is an excellent illustration of how our greater understanding of molecular cell death pathways can be translated into the clinic. Nevertheless, most venetoclax-treated patients will relapse, suggesting the need to target additional regulated cell death pathways. To highlight advances in this strategy, we review the recognized regulated cell death pathways, including apoptosis, necroptosis, ferroptosis and autophagy. Next, we detail the therapeutic opportunities to trigger regulated cell death in AML. Finally, we describe the main drug discovery challenges for regulated cell death inducers and their translation into clinical trials. A better knowledge of the molecular pathways regulating cell death represents a promising strategy to develop new drugs to cure resistant or refractory AML patients, particularly those resistant to intrinsic apoptosis.

BCL2 抑制剂 venetoclax 的使用改变了对不符合强化化疗条件的急性髓性白血病(AML)患者的治疗。该药物通过触发细胞内在凋亡,很好地诠释了我们如何将对细胞分子死亡途径的更深入了解应用于临床。尽管如此,大多数接受过 venetoclax 治疗的患者仍会复发,这表明有必要针对其他受调控的细胞死亡途径进行治疗。为了强调这一策略的进展,我们回顾了公认的调控细胞死亡途径,包括细胞凋亡、坏死、铁变性和自噬。接下来,我们将详细介绍在急性髓细胞性白血病中引发调节性细胞死亡的治疗机会。最后,我们介绍了调节性细胞死亡诱导剂的主要药物发现挑战及其转化为临床试验的情况。更好地了解调控细胞死亡的分子通路是开发治疗耐药或难治性急性髓细胞性白血病患者(尤其是对内在凋亡耐药的患者)新药的大有可为的策略。
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引用次数: 0
Cancer stem cells in drug resistance: an introduction to the e-book covering the special issue on the "Cancer Stem Cells and Drug Resistance". 癌症干细胞的耐药性:介绍电子书覆盖的特刊“癌症干细胞和耐药性”。
Q1 ONCOLOGY Pub Date : 2023-01-01 DOI: 10.20517/cdr.2023.23
Balázs Sarkadi
© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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引用次数: 0
How acute myeloid leukemia (AML) escapes from FMS-related tyrosine kinase 3 (FLT3) inhibitors? Still an overrated complication? 急性髓性白血病(AML)如何从fms相关酪氨酸激酶3 (FLT3)抑制剂中逃脱?还是一个被高估的并发症?
Q1 ONCOLOGY Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.130
Salvatore Perrone, Tiziana Ottone, Nadezda Zhdanovskaya, Matteo Molica

FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of apoptosis. Two types of FLT3 mutations exist: FLT3-ITD and FLT3-TKD (point mutations in D835 and I836 or deletion of codon I836). A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1st and 2nd generation molecules, but only midostaurin and gilteritinib are currently approved. However, the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma, as the duration of clinical responses is generally limited to a few months. This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon. Has resistance been overlooked? Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib).

fms相关酪氨酸激酶3 (FLT3)突变存在于约25%-30%的急性髓性白血病(AML)患者中,是这些患者中最常检测到的突变之一。FLT3L与FLT3结合可激活磷脂酰肌醇3-激酶(PI3K)和RAS通路,促进细胞增殖,抑制细胞凋亡。FLT3存在两种类型的突变:FLT3- itd和FLT3- tkd (D835和I836点突变或密码子I836缺失)。一类靶向突变FLT3的药物酪氨酸激酶抑制剂(TKI)已经有了第一代和第二代分子,但目前只有米多舒林和吉特替尼获得批准。然而,耐药的出现或对FLT3抑制剂无反应的克隆的选择已成为一个重要的临床难题,因为临床反应的持续时间通常限于几个月。这篇综述分析了对TKI耐药机制的见解,并对这一现象的临床相关性提出了特别的看法。抗药性被忽视了吗?事实上,FLT3抑制剂显著有助于减少FLT3突变对AML患者预后的负面影响,这些患者不再被欧洲白血病网(ELN) 2022视为高风险。最后,将介绍一些正在进行的克服FLT3抑制剂耐药的努力:新一代FLT3抑制剂单药或与标准化疗、低甲基化药物或IDH1/2抑制剂、Bcl2抑制剂联合使用;新型抗人FLT3单克隆抗体(如FLT3/CD3双特异性抗体);FLT3-CAR t细胞;CDK4/6激酶抑制剂(如帕博西尼)。
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引用次数: 2
Importance of ROS1 gene fusions in non-small cell lung cancer. ROS1基因融合在非小细胞肺癌中的重要性。
Q1 ONCOLOGY Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.105
Meri Muminovic, Carlos Rodrigo Carracedo Uribe, Andres Alvarez-Pinzon, Khine Shan, Luis E Raez
Targeted therapy has become one of the standards of care for advanced lung cancer. More than 10 genetic aberrations have been discovered that are actionable and several tyrosine kinase inhibitors (TKIs) have been approved to target each of them. Among several genetic aberrations that are actionable in non-small cell lung cancer (NSCLC), ROS1 translocations also known as gene fusion proteins, are found in only 1%-2% of the patient population. ROS1 mutations can usually be detected using a combination of techniques such as immunohistochemistry (IHC), Fluorescence in-situ testing (FISH), polymerase chain reaction (PCR), and next-generation sequencing (NGS). However, RNA NGS and ctDNA NGS (liquid biopsies) also contribute to the diagnosis. There are currently numerous FDA-approved agents for these tumors, including crizotinib and entrectinib; however, there is in-vitro sensitivity data and clinical data documenting responses to ceritinib and lorlatinib. Clinical responses and survival rates with these agents are frequently among the best compared to other TKIs with genetic aberrations; however, intrinsic or extrinsic mechanisms of resistance may develop, necessitating research for alternative treatment modalities. To combat the mechanisms of resistance, novel agents such as repotrectenib, cabozantinib, talotrectinib, and others are being developed. In this article, we examine the literature pertaining to patients with ROS1 tumors, including epidemiology, clinical outcomes, resistance mechanisms, and treatment options.
靶向治疗已成为晚期肺癌治疗的标准之一。已经发现了10多种可治疗的遗传畸变,并且已经批准了几种酪氨酸激酶抑制剂(TKIs)来针对每种畸变。在非小细胞肺癌(NSCLC)中可操作的几种遗传畸变中,ROS1易位也称为基因融合蛋白,仅在1%-2%的患者群体中发现。ROS1突变通常可以通过免疫组织化学(IHC)、荧光原位检测(FISH)、聚合酶链反应(PCR)和下一代测序(NGS)等技术的组合来检测。然而,RNA NGS和ctDNA NGS(液体活检)也有助于诊断。目前有许多fda批准的药物用于治疗这些肿瘤,包括克唑替尼和恩替尼;然而,有体外敏感性数据和临床数据记录了对ceritinib和lorlatinib的反应。与其他具有遗传畸变的tki相比,这些药物的临床反应和生存率通常是最好的;然而,内在或外在的耐药机制可能会发展,需要研究替代治疗方式。为了对抗耐药机制,正在开发诸如repotrectenib、cabozantinib、talotrectinib等新型药物。在这篇文章中,我们研究了与ROS1肿瘤患者有关的文献,包括流行病学、临床结果、耐药机制和治疗方案。
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引用次数: 1
期刊
癌症耐药(英文)
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