BRAF V600E型转移性结直肠癌治疗进展

转移性结直肠癌(metastatic colorectal cancer,mCRC)患者中约8%~15%存在BRAF基因突变,V600E是BRAF最常见的突变形式。BRAF V600E突变型的mCRC患者预后差,初始标准化疗效果不佳,强烈治疗的效果有限,并且在初始治疗失败后,后续治疗疗效甚微,疾病进展迅速,患者总生存期短,这类患者治疗现状不容乐观。因此,应寻找对于BRAF V600E突变型mCRC患者的更为有效治疗方案。本文将详细介绍BRAF V600E突变与mCRC患者预后及疗效预测方面的相关研究及治疗进展,以期为延长患者生存期提供参考依据。

Erratum to Simultaneous inhibition of PI3Kα and CDK4/6synergistically suppresses KRAS-mutated non-small cell lung cancer

In the published Figure 11,errors appeared in Figure 1B on page 69.In Figure 1B,bands for p-Akt S473,Akt,and Actin in H1355 cells were mistakenly placed.Here,we have updated Figure 1B to correct the mistake above.The errors do not impact the conclusions of this article.We apologize for the errors and for any confusion it may have caused.

Simultaneous inhibition of PI3Kα and CDK4/6 synergistically suppresses KRAS-mutated non-small cell lung cancer

Objective: Activating KRAS mutations are the most common drivers in the development of non-small cell lung cancer(NSCLC).However, unsuccess of treatment by direct inhibition of KRAS has been proven. Deregulation of PI3K signaling plays an important role in tumorigenesis and drug resistance in NSCLC. The activity of PI3Kα-selective inhibition against KRAS-mutated NSCLC remains largely unknown.Methods: Cell proliferation was detected by sulforhodamine B assay. Cell cycle distribution and apoptosis were measured by flow cytometry. Cell signaling was assessed by Western blot and immunohistochemistry. RNA interference was used to down-regulate the expression of cyclin D1. Human NSCLC xenografts were employed to detect therapeutic efficacy in vivo.Results: CYH33 possessed variable activity against a panel of KRAS-mutated NSCLC cell lines. Although CYH33 blocked AKT phosphorylation in all tested cells, Rb phosphorylation decreased in CYH33-sensitive, but not in CYH33-resistant cells, which was consistent with G1 phase arrest in sensitive cells. Combined treatment with the CDK4/6 inhibitor, PD0332991, and CYH33 displayed synergistic activity against the proliferation of both CYH33-sensitive and CYH33-resistant cells, which was accompanied by enhanced G1-phase arrest. Moreover, down-regulation of cyclin D1 sensitized NSCLC cells to CYH33. Reciprocally, CYH33 abrogated the PD0332991-induced up-regulation of cyclin D1 and phosphorylation of AKT in A549 cells. Co-treatment with these two drugs demonstrated synergistic activity against A549 and H23 xenografts, with enhanced inhibition of Rb phosphorylation.Conclusions: Simultaneous inhibition of PI3Kα and CDK4/6 displayed synergistic activity against KRAS-mutated NSCLC. These data provide a mechanistic rationale for the combination of a PI3Kα inhibitor and a CDK4/6 inhibitor for the treatment of KRASmutated NSCLC.

Intact regulation of G1/S transition renders esophageal squamous cell carcinoma sensitive to PI3Kαinhibitors

Phosphatidylinositol 3-kinase alpha(PI3Kα)inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma(ESCC).It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kαinhibitors in an aim to improve the clinical responsive rate in ESCC.Here,ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33,a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC.Elevated level of cyclin D1,p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells.CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase,which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2.Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1,which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21.Moreover,CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33.These findings provided mechanistic rationale to evaluate PI3Kαinhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.

Comparative genomic analysis of esophageal squamous cell carcinoma and adenocarcinoma:New opportunities towards molecularly targeted therapy

Esophageal cancer is one of the most lethal cancers worldwide because of its rapid progression and poor prognosis.Esophageal squamous cell carcinoma(ESCC)and esophageal adenocarcinoma(EAC)are two major subtypes of esophageal cancer.ESCC predominantly affects African and Asian populations,which is closely related to chronic smoking and alcohol consumption.EAC typically arises in Barrett’s esophagus with a predilection for Western countries.While surgical operation and chemoradiotherapy have been applied to combat this deadly cancer,molecularly targeted therapy is still at the early stages.With the development of large-scale next-generation sequencing,various genomic alterations in ESCC and EAC have been revealed and their potential roles in the initiation and progression of esophageal cancer have been studied.Potential therapeutic targets have been identified and novel approaches have been developed to combat esophageal cancer.In this review,we comprehensively analyze the genomic alterations in EAC and ESCC and summarize the potential role of the genetic alterations in the development of esophageal cancer.Progresses in the therapeutics based on the different tissue types and molecular signatures have also been reviewed and discussed.

PBKα inhibitor impairs AKT phosphorylation and synergizes with novel angiogenesis inhibitor AL3810 in human hepatocellular carcinoma

Dear Editor,Hepatocellular carcinoma(HCC)is the second leading cause of cancer-related death worldwide with a 5-year survival rate-50-80% after curative treatment,like surgery,targeted therapy plus TACE or RFA or local treatments,immunotherapy,and so on.1 The approval of several angiogenesis inhibitors,such as sorafenib,regorafenib,lenvatinib,and cabozantinib,have shown therapeutic potential for HCC treatment.However,the improvement of overall survival or progression-free survival is still limited based on angiogenesis inhibitor monotherapy at present.