BACKGROUND Immune checkpoint inhibitors have revolutionized the treatment of patients with unresectable metastatic malignant melanoma.In addition to systemic side effects,several usually mild ocular adverse effects ha...BACKGROUND Immune checkpoint inhibitors have revolutionized the treatment of patients with unresectable metastatic malignant melanoma.In addition to systemic side effects,several usually mild ocular adverse effects have been reported.We report a case of rarely reported vision-threatening bilateral panuveitis with serous retinal detachment,thickened choroid,and chorioretinal folds associated with dabrafenib and trametinib targeted therapy for B-Raf proto-oncogene serine/threonine kinase(BRAF)mutant metastatic cutaneous melanoma.CASE SUMMARY A 59-year-old female patient with metastatic melanoma treated with dabrafenib and trametinib presented with blurry vision and central scotoma lasting for 3 d in both eyes.Clinical examination and multimodal imaging revealed inflammatory cells in the anterior chamber,mild vitritis,bullous multiple serous retinal detachments,and chorioretinal folds in both eyes.Treatment with dabrafenib and trametinib was suspended,and the patient was treated with topical and intravenous corticosteroids followed by oral corticosteroid treatment with a tapering schedule.One and a half months after the disease onset,ocular morphological and functional improvement was noted.Due to the metastatic melanoma dissemination,BRAF/mitogen-activated protein kinase inhibitors were reintroduced and some mild ocular adverse effects reappeared,which later subsided after receiving oral corticosteroids.CONCLUSION Patients on combination therapy with dabrafenib and trametinib may rarely develop severe bilateral panuveitis with a good prognosis.Further studies have to establish potential usefulness of ophthalmological examination for asymptomatic patients.Furthermore,appropriate guidelines for managing panuveitis associated with dabrafenib and trametinib should be established.展开更多
MEK is a canonical effector of mutant KRAS;however,MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers.Here,we identified mitochondrial oxidative phosphorylation(OXPHOS)induction as a pr...MEK is a canonical effector of mutant KRAS;however,MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers.Here,we identified mitochondrial oxidative phosphorylation(OXPHOS)induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer(NSCLC)resistance to the clinical MEK inhibitor trametinib.Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment,satisfying their energy demand and protecting them from apoptosis.As molecular events in this process,the pyruvate dehydrogenase complex(PDHc)and carnitine palmitoyl transferase IA(CPTIA),two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation.Importantly,the co-administration of trametinib and IACS-010759,a clinical mitochondrial complex I inhibitor that blocks OXPHOS,significantly impeded tumor growth and prolonged mouse survival.Overall,our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.展开更多
1型神经纤维瘤病(neurofibromatosis type 1,NF1)是一种常见的遗传性神经皮肤综合征,发病率为1/3500,主要表现为皮肤、神经、骨骼等多个系统的肿瘤形成。NF1基因突变导致神经纤维蛋白功能丧失,受神经纤维蛋白负调控的Ras信号失去抑制,导...1型神经纤维瘤病(neurofibromatosis type 1,NF1)是一种常见的遗传性神经皮肤综合征,发病率为1/3500,主要表现为皮肤、神经、骨骼等多个系统的肿瘤形成。NF1基因突变导致神经纤维蛋白功能丧失,受神经纤维蛋白负调控的Ras信号失去抑制,导致MAPK信号通路组成型激活,该信号通路的异常激活与肿瘤微环境等机制促使NF1肿瘤发生。目前,主流的治疗方式包括针对Raf/MEK/ERK通路和/或mTOR通路的靶向抑制剂。近年来,对NF1的遗传学、临床特征、肿瘤起源、异常信号通路以及相关靶向抑制剂的疗效等方面的研究日益增多。深入了解NF1的病理生物学和分子机制将为开发更有效的靶向治疗方法提供坚实的基础。展开更多
The RAS-RAF-MEK-ERK signaling pathway(MAPK signaling pathway) plays a significant role in multiple pathological behaviors and is most frequently dysregulated in more than 30% of human cancers.As key elements in this p...The RAS-RAF-MEK-ERK signaling pathway(MAPK signaling pathway) plays a significant role in multiple pathological behaviors and is most frequently dysregulated in more than 30% of human cancers.As key elements in this pathway, MEK1/2 play crucial roles in tumorigenesis and the inhibition of apoptosis, which makes their inhibition an attractive antitumor strategy.Dozens of potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed that have produced substantial improvement in clinical outcomes over the past decade.However, the efficacy of these agents is limited, and response rates are variable in a wide range of tumors that harbor RAS and RAF mutations due to the development of resistance, which is derived mainly from the persistence of MAPK signaling and increased activation of the mutual feedback networks.Both intrinsic and acquired resistance to MEK inhibitors necessitates the synergistic targeting of both pathways to restore the therapeutic effects of a single agent.In this review, the significant role of the MAPK pathway in carcinogenesis and its therapeutic potential are comprehensively examined with a focus on MEK inhibitors.Then, the activation of feedback networks accompanying MEK inhibition is briefly reviewed.Combination strategies that involve the simultaneous inhibition of the original and resistance pathways are highlighted and elaborately described on the basis of the latest research progress.Finally, the obstacles to the development of MEK-related combination systems are discussed in order to lay the groundwork for their clinical application as frontline treatments for individual patients with MAPK-hyperactivated malignancies.展开更多
文摘BACKGROUND Immune checkpoint inhibitors have revolutionized the treatment of patients with unresectable metastatic malignant melanoma.In addition to systemic side effects,several usually mild ocular adverse effects have been reported.We report a case of rarely reported vision-threatening bilateral panuveitis with serous retinal detachment,thickened choroid,and chorioretinal folds associated with dabrafenib and trametinib targeted therapy for B-Raf proto-oncogene serine/threonine kinase(BRAF)mutant metastatic cutaneous melanoma.CASE SUMMARY A 59-year-old female patient with metastatic melanoma treated with dabrafenib and trametinib presented with blurry vision and central scotoma lasting for 3 d in both eyes.Clinical examination and multimodal imaging revealed inflammatory cells in the anterior chamber,mild vitritis,bullous multiple serous retinal detachments,and chorioretinal folds in both eyes.Treatment with dabrafenib and trametinib was suspended,and the patient was treated with topical and intravenous corticosteroids followed by oral corticosteroid treatment with a tapering schedule.One and a half months after the disease onset,ocular morphological and functional improvement was noted.Due to the metastatic melanoma dissemination,BRAF/mitogen-activated protein kinase inhibitors were reintroduced and some mild ocular adverse effects reappeared,which later subsided after receiving oral corticosteroids.CONCLUSION Patients on combination therapy with dabrafenib and trametinib may rarely develop severe bilateral panuveitis with a good prognosis.Further studies have to establish potential usefulness of ophthalmological examination for asymptomatic patients.Furthermore,appropriate guidelines for managing panuveitis associated with dabrafenib and trametinib should be established.
基金sponsored by the National Natural Science Foundation of China(82122045,82073073,81874207,and 81872418)Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20210802,China)+4 种基金MOE Key Laboratory of Biosystems Homeostasis&Protection(Zhejiang University,China)Science and Technology Commission of Shanghai Municipality(21S11902000,China)Jointed PI Program from Shanghai Changning Maternity and Infant Health Hospital(11300-412311-20033,China)ECNU Construction Fund of Innovation and Entrepreneurship Laboratory(44400-20201-532300/021,China)the ECNU multifunctional platform for innovation(011 and 004,China).
文摘MEK is a canonical effector of mutant KRAS;however,MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers.Here,we identified mitochondrial oxidative phosphorylation(OXPHOS)induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer(NSCLC)resistance to the clinical MEK inhibitor trametinib.Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment,satisfying their energy demand and protecting them from apoptosis.As molecular events in this process,the pyruvate dehydrogenase complex(PDHc)and carnitine palmitoyl transferase IA(CPTIA),two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation.Importantly,the co-administration of trametinib and IACS-010759,a clinical mitochondrial complex I inhibitor that blocks OXPHOS,significantly impeded tumor growth and prolonged mouse survival.Overall,our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.
文摘1型神经纤维瘤病(neurofibromatosis type 1,NF1)是一种常见的遗传性神经皮肤综合征,发病率为1/3500,主要表现为皮肤、神经、骨骼等多个系统的肿瘤形成。NF1基因突变导致神经纤维蛋白功能丧失,受神经纤维蛋白负调控的Ras信号失去抑制,导致MAPK信号通路组成型激活,该信号通路的异常激活与肿瘤微环境等机制促使NF1肿瘤发生。目前,主流的治疗方式包括针对Raf/MEK/ERK通路和/或mTOR通路的靶向抑制剂。近年来,对NF1的遗传学、临床特征、肿瘤起源、异常信号通路以及相关靶向抑制剂的疗效等方面的研究日益增多。深入了解NF1的病理生物学和分子机制将为开发更有效的靶向治疗方法提供坚实的基础。
基金funded by the Startup Foundation for Doctors of Shanxi Province (Grant No.SD1827)Startup Foundation for Doctors of Shanxi Medical University (Grant No.XD1824) to Y.Li+1 种基金National Natural Science Foundation of China (Grant No.81872147, 81572588)Guangdong Provincial Special Fund of Science Innovation Strategy (Grant No.180918104960680) to Y.Cui
文摘The RAS-RAF-MEK-ERK signaling pathway(MAPK signaling pathway) plays a significant role in multiple pathological behaviors and is most frequently dysregulated in more than 30% of human cancers.As key elements in this pathway, MEK1/2 play crucial roles in tumorigenesis and the inhibition of apoptosis, which makes their inhibition an attractive antitumor strategy.Dozens of potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed that have produced substantial improvement in clinical outcomes over the past decade.However, the efficacy of these agents is limited, and response rates are variable in a wide range of tumors that harbor RAS and RAF mutations due to the development of resistance, which is derived mainly from the persistence of MAPK signaling and increased activation of the mutual feedback networks.Both intrinsic and acquired resistance to MEK inhibitors necessitates the synergistic targeting of both pathways to restore the therapeutic effects of a single agent.In this review, the significant role of the MAPK pathway in carcinogenesis and its therapeutic potential are comprehensively examined with a focus on MEK inhibitors.Then, the activation of feedback networks accompanying MEK inhibition is briefly reviewed.Combination strategies that involve the simultaneous inhibition of the original and resistance pathways are highlighted and elaborately described on the basis of the latest research progress.Finally, the obstacles to the development of MEK-related combination systems are discussed in order to lay the groundwork for their clinical application as frontline treatments for individual patients with MAPK-hyperactivated malignancies.
