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晚期黑色素瘤靶向BRAF/MEK失败后PARP抑制剂治疗的疗效

Efficacy of PARP inhibitor therapy after targeted BRAF/MEK failure in advanced melanoma

Nature 等信源发布 2024-09-05 10:34

可切换为仅中文

AbstractModern advancements in targeted therapy and immunotherapy have significantly improved survival outcomes for advanced melanoma; however, there remains a need for novel approaches to overcome disease progression and treatment resistance. In recent years, PARPi therapy has shown great promise both as a single regimen and in combination with other therapeutics in melanoma.

摘要靶向治疗和免疫治疗的现代进展显着改善了晚期黑色素瘤的生存结果；然而，仍然需要新的方法来克服疾病进展和治疗耐药性。近年来，PARPi疗法作为单一疗法以及与黑色素瘤的其他疗法相结合都显示出巨大的前景。

Here, we describe three unique cases of advanced BRAF V600 mutated melanoma that progressed on targeted BRAF/MEK agents that subsequently exhibited partial to near-complete responses to combinatory PARPi and BRAF/MEK inhibitors. This highlights both a potential synergy underlying this combinatory approach and its efficacy as a treatment option for patients with advanced melanoma refractory to targeted and/or immunotherapies.

在这里，我们描述了三种独特的晚期BRAF V600突变黑色素瘤病例，这些病例在靶向BRAF/MEK药物上进展，随后对组合PARPi和BRAF/MEK抑制剂表现出部分至接近完全的反应。这突出了这种组合方法的潜在协同作用及其作为靶向和/或免疫疗法难治的晚期黑色素瘤患者的治疗选择的功效。

Prospective clinical trials are needed to explore this synergic effect in larger melanoma cohorts to investigate this combination for treating refractory advanced melanoma..

需要进行前瞻性临床试验来探索这种在较大黑色素瘤队列中的协同作用，以研究这种联合治疗难治性晚期黑色素瘤的方法。。

IntroductionMelanoma, the deadliest type of skin cancer, accounts for nearly 2% of all global cancer diagnoses and remains the fifth most common cancer in the US1. Alarmingly, the prevalence of the disease has increased drastically in recent years, with over 100,000 new cases and 8,000 deaths expected in 20242.

引言黑色素瘤是最致命的皮肤癌类型，占全球所有癌症诊断的近2%，仍然是美国第五大常见癌症1。令人担忧的是，近年来该病的患病率急剧上升，预计20242年将有超过100000例新病例和8000例死亡。

However, melanoma mortality, especially from advanced/metastatic disease, has dropped significantly due to modern advancements in immunotherapy and targeted therapies (e.g., BRAF, MEK, MAPK)1,2,3,4. Activating mutations in BRAF, which are present in about 50% of metastatic melanoma, are recognized as predictive biomarkers for targeted therapies in patients with advanced melanoma.

然而，由于免疫疗法和靶向疗法（例如BRAF，MEK，MAPK）1,2,3,4的现代进步，黑色素瘤死亡率，特别是晚期/转移性疾病的死亡率显着下降。BRAF中的激活突变存在于约50%的转移性黑色素瘤中，被认为是晚期黑色素瘤患者靶向治疗的预测性生物标志物。

Furthermore, nearly 50% of patients with advanced melanoma treated with immunotherapies, such as combination ipilimumab and nivolumab, remain alive at 7.5 years, a vast improvement over the prior era of cytotoxic chemotherapies and cytokine treatment5. In addition, the NEMO trial demonstrated that binimetinib, a MEK inhibitor, contributed to a significantly longer progression-free survival (2.8 months) compared to dacarbazine (1.5 months) in patients with NRAS-mutant advanced melanoma6.

此外，近50%接受免疫疗法治疗的晚期黑色素瘤患者，如联合ipilimumab和nivolumab，在7.5岁时仍然存活，这比之前的细胞毒性化学疗法和细胞因子治疗时代有了巨大的改善5。此外，NEMO试验表明，与达卡巴嗪（1.5个月）相比，MEK抑制剂binimetinib对NRAS突变型晚期黑色素瘤患者的无进展生存期（2.8个月）有显着延长6。

However, resistance and intolerance to both immunotherapy and targeted therapies are common and remain a challenge in advanced melanoma treatment7,8,9. Thus, novel therapeutics or combinatory approaches are required to overcome resistance and disease progression, especially in cases of advanced disease.Poly (ADP-Ribose) Polymerase inhibitors (PARPi) have emerged as a promising treatment in cancers with alterations in homologous recombination repair (HRR) genes, a type of DNA damage repair (also termed HR-DDR).

然而，对免疫疗法和靶向疗法的耐药性和不耐受性很常见，并且在晚期黑色素瘤治疗中仍然是一个挑战7,8,9。因此，需要新的治疗方法或组合方法来克服耐药性和疾病进展，特别是在晚期疾病的情况下。。

PARPi treatments work by creating double-stranded DNA (dsDNA) breaks that, under normal physiolo.

PARPi治疗通过在正常生理条件下产生双链DNA（dsDNA）断裂来起作用。

Data availability

数据可用性

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

本研究中使用和/或分析的数据集可根据合理要求从通讯作者处获得。

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Download referencesAcknowledgementsThe authors would like to thank the patients for their consent to publish their medical history. The authors would also like to thank Charuta Palsuledesai (and the Natera team) for their expertise on ctDNA methodology and compiling Fig. 1. This study received no funding.Author informationAuthor notesThese authors contributed equally: Jordan Phillipps, George Nassief.Authors and AffiliationsDivision of Medical Oncology, Department of Medicine, Washington University in Saint Louis, Saint Louis, MO 63130, USAJordan Phillipps, George Nassief, Renee Morecroft, Omar Butt, Alice Zhou & George AnsstasCaris Life Sciences, Phoenix, AZ, USATolulope Adeyelu, Andrew Elliott, Farah Abdulla & Ari VanderwaldeUniversity of California San Diego, San Diego, CA, USASoo ParkAuthorsJordan PhillippsView author publicationsYou can also search for this author in.

下载参考文献致谢作者要感谢患者同意发表病史。作者还要感谢Charuta Palsuledesai（和Natera团队）在ctDNA方法学和编译图1方面的专业知识。这项研究没有得到资助。作者信息作者注意到这些作者做出了同样的贡献：Jordan Phillipps，George Nassief。作者和附属机构华盛顿大学圣路易斯分校医学系肿瘤内科，密苏里州圣路易斯63130，USAJordan Phillipps，George Nassief，Renee Morecroft，Omar Butt，Alice Zhou＆George Anstascaris Life Sciences，Phoenix，AZ，USATollope Adeyelu，Andrew Elliott，Farah Abdulla＆Ari VanderwaldeUniversity of California San Diego，San Diego，CA，USASoo ParkAuthorsJordan PhillippsView作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarGeorge NassiefView author publicationsYou can also search for this author in

PubMed谷歌学术杂志NassiefView作者出版物您也可以在

PubMed Google ScholarRenee MorecroftView author publicationsYou can also search for this author in

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PubMed Google ScholarTolulope AdeyeluView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsJ.P., G.N., and R.M. performed literature review, extracted/analyzed patient data, and wrote/revised the manuscript. T.A., A.E., F.A., A.V., S.P., O.B. provided expertise in editing and revising the manuscript. G.A. conceived the project idea and approved the final manuscript.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献。P、 ，G.N.和R.M.进行了文献综述，提取/分析了患者数据，并撰写/修订了手稿。T、 A.，A.E.，F.A.，A.V.，S.P.，O.B.提供了编辑和修改稿件的专业知识。G、 A.构思了项目想法并批准了最终稿件。对应作者对应。

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Reprints and permissionsAbout this articleCite this articlePhillipps, J., Nassief, G., Morecroft, R. et al. Efficacy of PARP inhibitor therapy after targeted BRAF/MEK failure in advanced melanoma.

转载和许可本文引用本文Phillipps，J.，Nassief，G.，Morecroft，R。等人。晚期黑色素瘤靶向BRAF/MEK失败后PARP抑制剂治疗的疗效。

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