Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor ...Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor prognosis and tumour relapse contributed to the malignancies and difficulties in treating pancreatic cancer. The current standard chemotherapy for pancreatic cancer is gemcitabine, however its efficacy is far from satisfactory, one of the reasons is due to the complex tumour microenvironment which decreases effective drug delivery to target cancer cell. Studies of the molecular pathology of pancreatic cancer have revealed that activation of KRAS, overexpression of cyclooxygenase-2, inactivation of p16<sup>INK4A</sup> and loss of p53 activities occurred in pancreatic cancer. Co-administration of gemcitabine and targeting the molecular pathological events happened in pancreatic cancer has brought an enhanced therapeutic effectiveness of gemcitabine. Therefore, studies looking for novel targets in hindering pancreatic tumour growth are emerging rapidly. In order to give a better understanding of the current findings and to seek the direction in future pancreatic cancer research; in this review we will focus on targets suppressing tumour metastatsis and progression, KRAS activated downstream effectors, the relationship of Notch signaling and Nodal/Activin signaling with pancreatic cancer cells, the current findings of non-coding RNAs in inhibiting pancreatic cancer cell proliferation, brief discussion in transcription remodeling by epigenetic modifiers (e.g., HDAC, BMI1, EZH2) and the plausible therapeutic applications of cancer stem cell and hyaluronan in tumour environment.展开更多
HER3 belongs to the human epidermal growth factor receptor(HER) family which also includes HER1/EGFR/erb B1,HER2/erb B2,and HER4/erb B4. As a unique member of the HER family,HER3 lacks or has little intrinsic tyrosine...HER3 belongs to the human epidermal growth factor receptor(HER) family which also includes HER1/EGFR/erb B1,HER2/erb B2,and HER4/erb B4. As a unique member of the HER family,HER3 lacks or has little intrinsic tyrosine kinase activity. It frequently co-expresses and forms heterodimers with other receptor tyrosine kinases(RTKs) in cancer cells to activate oncogenic signaling,especially the PI-3 K/Akt pathway and Src kinase. Elevated expression of HER3 has been observed in a wide variety of human cancers and associates with a worse survival in cancer patients with solid tumors.Studies on the underlying mechanism implicate HER3 expression as a major cause of treatment failure in cancer therapy. Activation of HER3 signaling has also been shown to promote cancer metastasis. These data strongly support the notion that therapeutic inactivation of HER3 and/or its downstream signaling is required to overcome treatment resistance and improve the outcomes of cancer patients.展开更多
抗体偶联药物(antibody drug conjugations,ADCs)是一类兼具靶向特异性和化疗药物高活性的新型药物,逐渐成为新一代极具临床应用前景的治疗模式。近年来,在乳腺癌领域中,针对不同肿瘤细胞表面抗原的单抗和小分子强效细胞毒性药物组成的A...抗体偶联药物(antibody drug conjugations,ADCs)是一类兼具靶向特异性和化疗药物高活性的新型药物,逐渐成为新一代极具临床应用前景的治疗模式。近年来,在乳腺癌领域中,针对不同肿瘤细胞表面抗原的单抗和小分子强效细胞毒性药物组成的ADCs对复发/转移性乳腺癌展现出优越的治疗效果。本文就乳腺癌领域不同分子靶点的ADCs的临床应用及研究进展作一综述。展开更多
Lung cancer remains the leading cause of cancer-associated mortality worldwide,but with the emergence of oncogene targeted therapies,treatment options have tremendously improved.Owing to their biological relevance,mem...Lung cancer remains the leading cause of cancer-associated mortality worldwide,but with the emergence of oncogene targeted therapies,treatment options have tremendously improved.Owing to their biological relevance,members of the ERBB receptor family,including the EGF receptor(EGFR),HER2,HER3 and HER4,are among the best studied oncogenic drivers.Activating EGFR mutations are frequently observed in non-small cell lung cancer(NSCLC),and small molecule tyrosine kinase inhibitors(TKIs)are the established first line treatment option for patients whose tumors bear"typical/classical"EGFR mutations(exon 19 deletions,L858R point mutations).Additionally,new TKIs are rapidly evolving with better efficacy to overcome primary and secondary treatment resistance(e.g.,that due to T790M or C797S resistance mutations).Some atypical EGFR mutations,such as the most frequent exon 20 insertions,exhibit relative resistance to earlier generation TKIs through steric hindrance.In this subgroup,newer TKIs,such as mobocertinib and the bi-specific antibody amivantamab have recently been approved,whereas less frequent atypical EGFR mutations remain understudied.In contrast to EGFR,HER2 has long remained a challenging target,but better structural understanding has led to the development of newer generations of TKIs.The recent FDA approval of the antibody-drug conjugate trastuzumab-deruxtecan for pretreated patients with HER2 mutant NSCLC has been an important therapeutic breakthrough.HER3 and HER4 also exert oncogenic potential,and targeted treatment approaches are being developed,particularly for HER3.Overall,strategies to inhibit the oncogenic function of ERBB receptors in NSCLC are currently evolving at an unprecedented pace;therefore,this review summarizes current treatment standards and discusses the outlook for future developments.展开更多
Dimerization among the EGFR family of tyrosine kinase receptors leads to allosteric activation of the kinase domains of the partners.Unlike other members in the family,the kinase domain of HER3 lacks key amino acid re...Dimerization among the EGFR family of tyrosine kinase receptors leads to allosteric activation of the kinase domains of the partners.Unlike other members in the family,the kinase domain of HER3 lacks key amino acid residues for catalytic activity.As a result,HER3 is suggested to serve as an allosteric activator of other EGFR family members which include EGFR,HER2 and HER4.To study the role of intracellular domains in HER3 dimerization and activation of downstream signaling pathways,we constructed HER3/HER2 chimeric receptors by replacing the HER3 kinase domain(HER3-2-3)or both the kinase domain and the C-terminal tail(HER3-2-2)with the HER2 counterparts and expressed the chimeric receptors in Chinese hamster ovary(CHO)cells.While over expression of the intact human HER3 transformed CHO cells with oncogenic properties such as AKT/ERK activation and increased proliferation and migration,CHO cells expressing the HER3-2-3 chimeric receptor showed significantly reduced HER3/HER2 dimerization and decreased phosphorylation of both AKT and ERK1/2 in the presence of neuregulin-1(NRG-1).In contrast,CHO cells expressing the HER3-2-2 chimeric receptor resulted in a total loss of downstream AKT activation in response to NRG-1,but maintained partial activation of ERK1/2.The results demonstrate that the intracellular domains play a crucial role in HER3’s function as an allosteric activator and its role in downstream signaling.展开更多
Over the past two decades,high sensitivity to HER2-amplified primary breast cancers has been achieved with HER2-targeted therapies.CDK4/6 inhibitors have long been identified as a potential treatment option for advanc...Over the past two decades,high sensitivity to HER2-amplified primary breast cancers has been achieved with HER2-targeted therapies.CDK4/6 inhibitors have long been identified as a potential treatment option for advanced breast cancer patients.However,acquired HER2 heterogeneity leading to resistance during the treatment has been identified as a bottleneck.This review focuses on the recent resistance mechanisms identified and potential therapeutic targets for conventional and combination endocrine therapies with CDK4/6 inhibitors by various breast cancer clinical trials and research groups in HER amplified and/or mutated breast cancer tumour.Activating HER2 alterations,JNK pathway,hyperactivated TORC1,co-mutations in HER2 and HER3,phenotypic changes of HER2,and few other advanced findings are identified as potential therapeutic targets in treating current HER2 endocrine therapy-resistant tumour.Along with the HER2-focused resistance mechanisms,we also describe how the microbiome may play a role in breast cancer therapy and its potential for new therapeutic strategies to overcome drug resistance in breast cancers.展开更多
文摘Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor prognosis and tumour relapse contributed to the malignancies and difficulties in treating pancreatic cancer. The current standard chemotherapy for pancreatic cancer is gemcitabine, however its efficacy is far from satisfactory, one of the reasons is due to the complex tumour microenvironment which decreases effective drug delivery to target cancer cell. Studies of the molecular pathology of pancreatic cancer have revealed that activation of KRAS, overexpression of cyclooxygenase-2, inactivation of p16<sup>INK4A</sup> and loss of p53 activities occurred in pancreatic cancer. Co-administration of gemcitabine and targeting the molecular pathological events happened in pancreatic cancer has brought an enhanced therapeutic effectiveness of gemcitabine. Therefore, studies looking for novel targets in hindering pancreatic tumour growth are emerging rapidly. In order to give a better understanding of the current findings and to seek the direction in future pancreatic cancer research; in this review we will focus on targets suppressing tumour metastatsis and progression, KRAS activated downstream effectors, the relationship of Notch signaling and Nodal/Activin signaling with pancreatic cancer cells, the current findings of non-coding RNAs in inhibiting pancreatic cancer cell proliferation, brief discussion in transcription remodeling by epigenetic modifiers (e.g., HDAC, BMI1, EZH2) and the plausible therapeutic applications of cancer stem cell and hyaluronan in tumour environment.
基金supported in part by a grant from the National Institutes of Health (NIH), USA (R01CA201011 to BL)a grant from the National Natural Science Foundation of China (81472763 to BL)
文摘HER3 belongs to the human epidermal growth factor receptor(HER) family which also includes HER1/EGFR/erb B1,HER2/erb B2,and HER4/erb B4. As a unique member of the HER family,HER3 lacks or has little intrinsic tyrosine kinase activity. It frequently co-expresses and forms heterodimers with other receptor tyrosine kinases(RTKs) in cancer cells to activate oncogenic signaling,especially the PI-3 K/Akt pathway and Src kinase. Elevated expression of HER3 has been observed in a wide variety of human cancers and associates with a worse survival in cancer patients with solid tumors.Studies on the underlying mechanism implicate HER3 expression as a major cause of treatment failure in cancer therapy. Activation of HER3 signaling has also been shown to promote cancer metastasis. These data strongly support the notion that therapeutic inactivation of HER3 and/or its downstream signaling is required to overcome treatment resistance and improve the outcomes of cancer patients.
文摘抗体偶联药物(antibody drug conjugations,ADCs)是一类兼具靶向特异性和化疗药物高活性的新型药物,逐渐成为新一代极具临床应用前景的治疗模式。近年来,在乳腺癌领域中,针对不同肿瘤细胞表面抗原的单抗和小分子强效细胞毒性药物组成的ADCs对复发/转移性乳腺癌展现出优越的治疗效果。本文就乳腺癌领域不同分子靶点的ADCs的临床应用及研究进展作一综述。
基金supported by the German Cancer Aid Foundation (Deutsche Krebshilfe, Grant Nos. 70112835, 70113510 and 70114428 to nNGM)the Hector Foundation Ⅱ to SL
文摘Lung cancer remains the leading cause of cancer-associated mortality worldwide,but with the emergence of oncogene targeted therapies,treatment options have tremendously improved.Owing to their biological relevance,members of the ERBB receptor family,including the EGF receptor(EGFR),HER2,HER3 and HER4,are among the best studied oncogenic drivers.Activating EGFR mutations are frequently observed in non-small cell lung cancer(NSCLC),and small molecule tyrosine kinase inhibitors(TKIs)are the established first line treatment option for patients whose tumors bear"typical/classical"EGFR mutations(exon 19 deletions,L858R point mutations).Additionally,new TKIs are rapidly evolving with better efficacy to overcome primary and secondary treatment resistance(e.g.,that due to T790M or C797S resistance mutations).Some atypical EGFR mutations,such as the most frequent exon 20 insertions,exhibit relative resistance to earlier generation TKIs through steric hindrance.In this subgroup,newer TKIs,such as mobocertinib and the bi-specific antibody amivantamab have recently been approved,whereas less frequent atypical EGFR mutations remain understudied.In contrast to EGFR,HER2 has long remained a challenging target,but better structural understanding has led to the development of newer generations of TKIs.The recent FDA approval of the antibody-drug conjugate trastuzumab-deruxtecan for pretreated patients with HER2 mutant NSCLC has been an important therapeutic breakthrough.HER3 and HER4 also exert oncogenic potential,and targeted treatment approaches are being developed,particularly for HER3.Overall,strategies to inhibit the oncogenic function of ERBB receptors in NSCLC are currently evolving at an unprecedented pace;therefore,this review summarizes current treatment standards and discusses the outlook for future developments.
基金partially funded by grants from the Texas Emerging Technology Fund and the Welch Foundation.
文摘Dimerization among the EGFR family of tyrosine kinase receptors leads to allosteric activation of the kinase domains of the partners.Unlike other members in the family,the kinase domain of HER3 lacks key amino acid residues for catalytic activity.As a result,HER3 is suggested to serve as an allosteric activator of other EGFR family members which include EGFR,HER2 and HER4.To study the role of intracellular domains in HER3 dimerization and activation of downstream signaling pathways,we constructed HER3/HER2 chimeric receptors by replacing the HER3 kinase domain(HER3-2-3)or both the kinase domain and the C-terminal tail(HER3-2-2)with the HER2 counterparts and expressed the chimeric receptors in Chinese hamster ovary(CHO)cells.While over expression of the intact human HER3 transformed CHO cells with oncogenic properties such as AKT/ERK activation and increased proliferation and migration,CHO cells expressing the HER3-2-3 chimeric receptor showed significantly reduced HER3/HER2 dimerization and decreased phosphorylation of both AKT and ERK1/2 in the presence of neuregulin-1(NRG-1).In contrast,CHO cells expressing the HER3-2-2 chimeric receptor resulted in a total loss of downstream AKT activation in response to NRG-1,but maintained partial activation of ERK1/2.The results demonstrate that the intracellular domains play a crucial role in HER3’s function as an allosteric activator and its role in downstream signaling.
文摘Over the past two decades,high sensitivity to HER2-amplified primary breast cancers has been achieved with HER2-targeted therapies.CDK4/6 inhibitors have long been identified as a potential treatment option for advanced breast cancer patients.However,acquired HER2 heterogeneity leading to resistance during the treatment has been identified as a bottleneck.This review focuses on the recent resistance mechanisms identified and potential therapeutic targets for conventional and combination endocrine therapies with CDK4/6 inhibitors by various breast cancer clinical trials and research groups in HER amplified and/or mutated breast cancer tumour.Activating HER2 alterations,JNK pathway,hyperactivated TORC1,co-mutations in HER2 and HER3,phenotypic changes of HER2,and few other advanced findings are identified as potential therapeutic targets in treating current HER2 endocrine therapy-resistant tumour.Along with the HER2-focused resistance mechanisms,we also describe how the microbiome may play a role in breast cancer therapy and its potential for new therapeutic strategies to overcome drug resistance in breast cancers.
