蛋白酪氨酸激酶小分子抑制剂研究进展

对近年来文献报道的小分子蛋白酪氨酸激酶(protein tyrosine kinases,PTKs)抑制剂按其结构类别进行综述.指出PTKs与肿瘤形成、生长过程有密切关系,已成为抗肿瘤研究的一个新靶点.在过去的30多年时间里,人们对大量的天然产物及人工合成化合物进行筛选,得到了许多小分子抑制剂,一些活性强、选择性高的化合物作为抗肿瘤药已进入开发研究的不同阶段,有的正在进行临床研究.     

Adjuvant therapy in renal cell carcinoma

Several drugs have demonstrated clinical activity in metastatic renal cell carcinoma (mRCC). The identification of key metabolic pathways has led to the development of novel targeted therapies which have drastically changed the treatment paradigm of mRCC. Moreover, immune-checkpoint inhibitors have recently shown significant activity in advanced disease. Despite these advancements, the role of adjuvant therapy in localized, non-metastatic RCC remains unclear. The utility of many of these agents in the adjuvant setting is currently being actively explored. In this review, we will summarize the main clinical trials investigating adjuvant therapy in renal cell carcinoma, focusing primarily on immunotherapy and targeted agents.     

C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK)—endogenous negative regulators of Src-family protein kinases

C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) are endogenous inhibitors of the Src-family protein tyrosine kinases (SFKs). Since constitutive activation of SFKs contributes to cancer formation and progression, to prevent excessive activation of SFKs, their activity in normal cells is kept at the basal level by CSK and CHK. CSK and CHK inactivate SFKs by specifically phosphorylating a consensus tyrosine (called Y_T) near their C-termini. Upon phosphorylation, the phospho-Y_T engages in intramolecular interactions that lock the SFK molecule in an inactive conformation. SFKs are anchored to the plasma membrane, while CSK and CHK are localized predominantly in the cytosol. To inhibit SFKs, CSK and CHK need to translocate to the plasma membrane. Recruitment of CSK and CHK to the plasma membrane is mediated by the binding of their SH2, SH3 and/or kinase domains to specific transmembrane proteins, G-proteins and adaptor proteins located near the plasma membrane. For CSK, membrane recruitment often accompanies activation. CSK and CHK employ two types of direct interactions with SFKs to achieve efficient Y_T phosphorylation: (i) short-range interactions involving binding of the active sites of CSK and CHK to specific residues near Y_T, (ii) long-range non-catalytic interactions involving binding of SFKs to motifs located distally from the active sites of CSK and CHK. The interactions between CSK and SFKs are transient in nature. Unlike CSK, CHK binds tightly to SFKs to form stable protein complexes. The binding is non-catalytic as it is independent of Y_T. More importantly, the tight binding alone is sufficient to completely inhibit SFKs. This non-catalytic inhibitory binding represents a novel mechanism employed by CHK to inhibit SFKs. Given that SFKs are implicated in cancer development, compounds mimicking the non-catalytic inhibitory mechanism of CHK are potential anti-cancer therapeutics.     

Elevated Src family kinase activity stabilizes E-cadherin-based junctions and collective movement of head and neck squamous cell carcinomas

EGF receptor (EGFR) overexpression is thought to drive head and neck carcinogenesis however clinical responses to EGFR-targeting agents have been modest and alternate targets are actively sought to improve results. Src family kinases (SFKs), reported to act downstream of EGFR are among the alternative targets for which increased expression or activity in epithelial tumors is commonly associated to the dissolution of E-cadherin-based junctions and acquisition of a mesenchymal-like phenotype. Robust expression of total and activated Src was observed in advanced stage head and neck tumors (N=60) and in head and neck squamous cell carcinoma lines. In cultured cancer cells Src co-localized with E-cadherin in cell-cell junctions and its phosphorylation on Y419 was both constitutive and independent of EGFR activation. Selective inhibition of SFKs with SU6656 delocalized E-cadherin and disrupted cellular junctions without affecting E-cadherin expression and this effect was phenocopied by knockdown of Src or Yes. These findings reveal an EGFR-independent role for SFKs in the maintenance of intercellular junctions, which likely contributes to the cohesive invasion E-cadherin-positive cells in advanced tumors. Further, they highlight the need for a deeper comprehension of molecular pathways that drive collective cell invasion, in absence of mesenchymal transition, in order to combat tumor spread.     

Personalized medicine for non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) is a heterogeneous illness associated with a high mortality rate. Personalized therapy may improve treatment outcomes by identification of a specific genotypic anomaly and target-specific therapy. The most significant development in recent years was the discovery of activated EGF receptor (EGFR) mutations at exons 19 and 21. Patients with EGFR mutations respond dramatically to EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib, resulting in longer progression-free survival. Multiple randomized studies, including the Iressa Pan-Asia Study and WJTOG3405, have confirmed the role of EGFR tyrosine kinase inhibitors as standard first-line therapy for patients with the EGFR mutation. In this article, we summarize the current nonpersonalized therapies and examine the available and investigational personalized therapies for patients with resectable early-stage, unresectable locally advanced, or metastatic disease.     

Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches.The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes.Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy.This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.     

Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [¹²⁵I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.     

The inhibition of TNF‐α‐induced leucocyte apoptosis by melatonin involves membrane receptor MT1/MT2 interaction

The pro‐apoptotic signalling cascades induced by tumour necrosis factor‐alpha (TNF‐α) have been intensively studied in multiple cellular systems. So far, it is known that TNF‐α can simultaneously activate survival and apoptotic cell death responses. The balance between these signals determines the ultimate response of the cell to TNF‐α. Moreover, emerging evidence suggests that melatonin may be involved in the protection of different cell types against apoptosis. Thus, the objective of this study was to evaluate the effect of melatonin on TNF‐α‐induced apoptosis in human leucocytes. Cells were treated with TNF‐α alone or in the presence of cycloheximide (CHX), which promotes caspase‐8 activation by eliminating the endogenous caspase‐8 inhibitor, c‐FLIP. Treatment with TNF‐α/CHX led to apoptotic cell death, as ascertained by annexin V/propidium iodide (PI) staining. Likewise, in the presence of CHX, TNF‐α stimulation produced cFLIP down‐regulation and subsequent caspase‐8 activation, thus directly triggering caspase‐3 activation and causing Bid truncation and subsequent caspase‐9 activation. Conversely, pre‐incubation of cells with melatonin inhibited TNF‐α‐/CHX‐evoked leucocyte apoptosis. Similarly, pretreatment of leucocytes with melatonin increased cFLIP protein levels, thereby preventing TNF‐α‐/CHX‐mediated caspase processing. Blockade of melatonin membrane receptor MT1/MT2 or extracellular signal‐regulated kinase (ERK) pathway with luzindole or PD98059, respectively, abolished the inhibitory effects of melatonin on leucocyte apoptosis evoked by TNF‐α/CHX. In conclusion, the model proposed by these findings is that the MT1/MT2 receptors, which are under the positive control of melatonin, trigger an ERK‐dependent signalling cascade that interferes with the anti‐apoptotic protein cFLIP modulating the cell life/death balance of human leucocytes.