Systematic analysis of DNA polymerases as therapeutic targets in pan-cancers

Introduction:DNA polymerases are crucial for maintaining genome stability and influencing tumorigenesis.However,the clinical implications of DNA polymerases in tumorigenesis and their potential as anti-cancer therapy targets are not well understood.Methods:We conducted a systematic analysis using TCGA Pan-Cancer Atlas data and Gene Set Cancer Analysis results to examine the expression profiles of 15 DNA polymerases(POLYs)and their clinical correlations.We also evaluated the prognostic value of POLYs by analyzing their expression levels in relation to overall survival time(OS)using Kaplan-Meier survival curves.Additionally,we investigated the correlations between POLY expression and immune cells,DNA damage repair(DDR)pathways,and ubiquitination.Drug sensitivity analysis was performed to assess the relationship between POLY expression and drug response.Results:Our analysis revealed that 14 out of 15 POLYs exhibited significantly distinct expression patterns between tumor and normal samples across most cancer types,except for DNA nucleotidylexotransferase(DNTT).Specifically,POLD1 and POLE showed elevated expression in almost all cancers,while POLQ exhibited high expression levels in all cancer types.Some POLYs showed heightened expression in specific cancer subtypes,while others exhibited low expression.Kaplan-Meier survival curves demonstrated significant prognostic value of POLYs in multiple cancers,including PAAD,KIRC,and ACC.Cox analysis further validated these findings.Alteration patterns of POLYs varied significantly among different cancer types and were associated with poorer survival outcomes.Significant correlations were observed between the expression of POLY members and immune cells,DDR pathways,and ubiquitination.Drug sensitivity analysis indicated an inverse relationship between POLY expression and drug response.Conclusion:Our comprehensive study highlights the significant role of POLYs in cancer development and identifies them as promising prognostic and immunological biomarkers for various cancer types.Additionally,targeting POLYs therapeutically holds promise for tumor immunotherapy.

Transcriptomic Analysis of Metastatic Colorectal Tumor with Low Mutational Burden

Objective:To identify potential drug targets for metastasis colorectal cancer(CRC)patients with low mutational burden by examining differences in immune-related gene expression.Methods:For this study,623 samples were collected from The Cancer Genome Atlas(TCGA)database,comprising tumor mutational burden(TMB),RNA sequencing(RNA-Seq),and clinical data.Differential gene expression analysis,Gene Ontology(GO),and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis of the identified genes were conducted using the R package.Additionally,a comparative analysis of immune infiltrating cell composition in metastatic and non-metastatic groups was performed.Hub genes,exhibiting high levels of interaction,were selected using the Search Tool for the Retrieval of Interacting Genes/Proteins(STRING)database.The Drug Gene Interaction Database(DGIdb)was then utilized to estimate drugs targeting the identified hub genes.Results:The transcriptome data of 326 colorectal cancer patients with low TMB were analyzed,comprising 58 patients with metastasis and 268 patients without metastasis.Among the differential expression in 1,111 genes for patients with metastasis compared to those without metastasis,733 genes were upregulated,and 378 genes were downregulated.KEGG and GO enrichment analysis indicated significant differences in gene expression in CRC metastatic patients with low TMB compared to non-metastasis patients with low TMB.Enriched pathways included humoral immune response,immunoglobulin production,and regulation of AMPA receptor activity.Two genes related to interleukin-12 were identified through secondary enrichment for immune-related genes.Analysis of tumor-infiltrating immune cell data revealed significant differences in memory-activated T cell CD4 and T cell CD8.Conclusions:This analysis of RNA sequencing data and immune-filtrating cell data revealed significant differences between metastatic colorectal cancer patients with low TMB and their non-metastatic counterparts.These distinctions suggest the possibility of identifying more effective drugs or therapies for metastatic colorectal cancer patients with low TMB.

The advanced development of molecular targeted therapy for hepatocellular carcinoma

Hepatocellular carcinoma(HCC),one of the most common malignant tumors in China,severely threatens the life and health of patients.In recent years,precision medicine,clinical diagnoses,treatments,and innovative research have led to important breakthroughs in HCC care.The discovery of new biomarkers and the promotion of liquid biopsy technologies have greatly facilitated the early diagnosis and treatment of HCC.Progress in targeted therapy and immunotherapy has provided more choices for precise HCC treatment.Multiomics technologies,such as genomics,transcriptomics,and metabolomics,have enabled deeper understanding of the occurrence and development mechanisms,heterogeneity,and genetic mutation characteristics of HCC.The continued promotion and accurate typing of HCC,accurate guidance of treatment,and accurate prognostication have provided more treatment opportunities and prolonged survival timelines for patients with HCC.Innovative HCC research providing an in-depth understanding of the biological characteristics of HCC will be translated into accurate clinical practices for the diagnosis and treatment of HCC.

Achievement of complete response to nivolumab in a patient with advanced sarcomatoid hepatocellular carcinoma:A case report

BACKGROUND Sarcomatoid hepatocellular carcinoma(SHC)is a rare subtype of hepatocellular carcinoma(HCC),with a high recurrence rate after surgery.In addition to limited effective treatment for the advanced stage of SHC,the prognosis of patients with this malignancy is worse than that of patients with conventional HCC.CASE SUMMARY We present the case of a 54-year-old man with SHC who underwent radical segmental hepatectomy,which relapsed 4 mo after surgery due to lymphatic metastasis in the porta hepatis.Although a second surgery was performed,new metastasis developed in the mediastinal lymph nodes.Therefore,sorafenib and lenvatinib were sequentially administered as first-and second-line systemic therapies,respectively.However,progressive disease was confirmed based on a recurrent hepatic lesion and new metastatic lesion in the abdominal cavity.Percutaneous transhepatic cholangial drainage was performed to alleviate the biliary obstruction.Because the tumor was strongly positive for programmed death-ligand 1,the patient was started on nivolumab.Imaging studies revealed that after two cycles of immunotherapy,the metastatic lesions decreased to undetectable levels.CONCLUSION The patient experienced continuous complete remission for 8 mo.Immune checkpoint inhibitors are useful for the treatment of advanced SHC.

Benefit of everolimus in treatment of an intrahepatic cholangiocarcinoma patient with a PIK3CA mutation

Intrahepatic cholangiocarcinoma(ICC) is a relatively rare form of liver cancer with a poor prognosis. The therapeutic options for patients with advanced ICC are limited and usually ineffective. There is currently no approved targeted therapy for ICC, although accumulating evidence supports inhibition of the PI3K/Akt/m TOR signaling pathway as a promising therapeutic strategy in the treatment of ICC. Here, we report a patient with stage IV ICC harboring a PIK3 CA mutation who responded well to the m TOR inhibitor everolimus. Computed tomography and magnetic resonance imaging demonstrated shrinkage of the tumor and maintenance of a partial response for 6.5 mo after everolimus treatment as the best response. To the best of our knowledge, this is the first clinical case report in the literature of clinical benefit from everolimus treatment in an ICC patient with PIK3 CA mutation.

Trastuzumab,not lapatinib,has therapeutic effects on Chinese patients with HER2-positive cholangiocarcinoma

As a relatively uncommon orphan tumor with high mortality,biliary tract cancer(BTC)presents an aggressive course and heterogeneous clinical features[1].BTC patients present with advanced manifestations[2].Unfortunately,there has been little progress in the management of BTC.Most patients have inoperable lesions and must receive palliative therapy.Gemcitabine-based chemotherapy has been the only widely accepted first-line treatment for advanced BTC[3].Nevertheless,BTCs are often refractory to chemotherapeutic regimens,leading to a poor clinical outcome in these patients.Recently,with the rapid development of next generation sequencing(NGS)technologies,some actionable mutations such as those in IDH1,FGFR2,BRAF,HER2 genes,and unique molecular subsets in BTCs have been identified[4],and related targeted therapy against actionable mutations has been introduced into clinical practice as a promising therapeutic strategy[5].

First-line camrelizumab(a PD-1 inhibitor)plus apatinib(an VEGFR-2 inhibitor)and chemotherapy for advanced gastric cancer(SPACE):a phase 1 study

Patients with advanced gastric cancer typically face a grim prognosis.This phase 1a(dose escalation)and phase 1b(dose expansion)study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapyfor advanced gastric or gastroesophageal junction adenocarcinoma.The primary endpoints included maximum tolerated dose(MTD)in phase 1a and objective response rate(ORR)across phase 1a and 1b.Phase 1a tested three dose regimens of camrelizumab,apatinib,oxaliplatin,and S-1.Dose regimen 1:camrelizumab 200 mg on day 1,apatinib 250 mg every other day,oxaliplatin 100 mg/m^(2) on day 1,and S-140 mg twice a day on days 1-14.Dose regimen 2:same as dose regimen 1,but oxaliplatin 130mg/m.Dose regimen3:same as dose regimen 2,but apatinib 250 mg daily.Thirty-four patients were included(9 in phase 1a,25 in phase 1b).No dose-limiting toxicities occurred so no MTD was identified.Dose 3 was set for the recommended phase 2 doses and administered in phase 1b.The confrmed ORR was 76.5%(95%CI 58.8-89.3).The median progression-free survival was 8.4 months(95%CI 5.9-not evaluable[NE]),and the median overall survival(OS)was not mature(11.6-NE).Ten patients underwent surgery after treatment and the multidisciplinary team evaluation.Among 24 patients without surgery,the median OS was 19.6 months(7.8-NE).Eighteen patients(52.9%)developed grade≥3 treatment-emergent adverse events.Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer(ChiCTR2000034109).

Loss of chromosome 9p21 is associated with a poor prognosis in adenosquamous carcinoma of the pancreas

Adenosquamous carcinoma of the pancreas(ASCP)is a rare histological subtype of pancreatic cancer with a poor prognosis and a high metastasis rate.However,little is known about its genomic landscape and prognostic biomarkers.A total of 48 ASCP specimens and 98 pancreatic ductal adenocarcinoma(PDAC)tumour specimens were sequenced to explore the genomic landscape and prognostic biomarkers.The homozygous deletion of the 9p21.3 region(including CDKN2A,CDKN2B,and MTAP)(9p21 loss)occurred in both ASCP and PDAC,and a higher frequency of 9p21 loss was observed in ASCP(12.5%vs 2.0%,P=0.022).Notably,9p21 loss was significantly associated with poor disease-free survival(DFS)in ASCP patients(mDFS(Median DFS)=4.17 vs 7.33 months,HR(Hazard Ratio)=3.70,P=0.009).The most common gene alterations in patients with ASCP were KRAS(96%),TP53(81%),CDKN2A(42%),SMAD4(21%),CDKN2B(13%),and FAT3(13%).The mutation rates of ACVR2A(6.25%vs 0%),FANCA(6.25%vs 0%),RBM10(6.25%vs 0%),and SPTA1(8.33%vs 1.02%)were significantly higher in ASCP than in PDAC.In conclusion,we have comprehensively described the genomic landscape of the largest cohort of ASCP patients to date and highlight that 9p21 loss may be a promising prognostic biomarker for ASCP,which provides a molecular basis for prognosis prediction and new therapeutic strategies for ASCP.

Personalized treatment based on mini patient-derived xenografts and WES/RNA sequencing in a patient with metastatic duodenal adenocarcinoma

Background:Treatment guidelines for a variety of cancers have been increasingly used in clinical practice,and have resulted in major improvement in patient outcomes.However,recommended regimens(even first-line treat-ments)are clearly not ideal for every patients.In the present study,we used mini patient-derived xenograft(mini-PDX)and next-generation sequencing to develop personalized treatment in a patient with metastatic duodenal adenocarcinoma.Methods:Resected metachronous metastatic tumor tissues were implanted into SCID mice to determine the sensitivity to a variety of drug regimens.Mutation profiles were assessed using both DNA whole-exome sequencing(DNA-WES)and RNA sequencing.The results of the analyses were used to select optimal treatment for the patient with metastatic duodenal adenocarcinoma.Results:Assessment with mini-PDX models took only 7 days.The results showed high sensitivity to S-1 plus cis-platin,gemcitabine plus cisplatin and everolimus alone.The patient received gemcitabine plus cisplatin initially,but the treatment was terminated due to toxicity.The patient was then switched to treatment with S-1 alone.The overall disease-free survival was 34 months.DNA-WES and RNA sequencing identified KRAS mutation(A146T),TP53(C229Yfs*10)and RICTOR amplification in the metastatic duodenal adenocarcinoma.These findings provided further support to the results of the mini-PDX,and suggest mTOR inhibitors should be used if and when relapse eventually occurs in this patient.Conclusions:Mini-PDX model combined with WES/RNA sequencing can rapidly assess drug sensitivity in cancer patients and reveal key genetic alterations.Further research on this technology for personalized therapy in patients with refractory malignant tumors is warranted.

Genomic profiling and the impact of MUC19 mutation in hepatoid adenocarcinoma of the stomach

Dear Editor,Hepatoid adenocarcinoma(HAC)is a rare pathological subtype of extrahepatic tumor,featured by hepatoid differentiation andα-fetoprotein(AFP)-production[1,2].Hepatoid adenocarcinoma of the stomach(HAS),accounting for 0.3%to 1.0%of all gastric cancers(GCs),has attracted increasing attention due to its high degree of malignancy[3].Compared with classic GC,HAS showed a higher rate of vascular invasion,lymph node metastasis,and liver metastasis,with only 9.0%survival rate at 5 years[4].Currently,there is no effective treatment for HAS,and little is known about its pathogenesis.Herein,we investigated the molecular features of HAS and identified potential therapeutic targets for HAS.

Pembrolizumab combined with lenvatinib as non-first-line therapy in patients with refractory biliary tract carcinoma

Background:A therapeutic strategy involving combined treatment with lenvatinib plus pembrolizumab(LEP)has demonstrated a relatively high antitumor response in several solid tumors;however,the efficacy and safety of LEP in patients with refractory bile tract carcinoma(BTC)remains unknown.Methods:This is a single-arm study for a preliminary assessment of the efficacy and tolerability of LEP in patients who experienced progression from prior systemic treatments.Pre-treatment tumor tissues were collected to retrospectively evaluate the expression status of PDL1.Results:Thirty-two patients received second-line and above treatment with LEP.Overall,the objective response rate(ORR)was 25%,the disease control rate(DCR)was 78.1%,and the clinical benefit rate(CBR)was 40.5%.The median progression-free survival(PFS)was 4.9 months(95%CI:4.7–5.2 months),and the median overall survival(OS)was 11.0 months(95%CI:9.6–12.3 months).For tolerability,no grade 5 serious adverse events(AEs)were reported.All patients had any-grade AEs,and 59.3%of the patients experienced grade 3 AEs,while only 1 patient experienced a grade 4 AE of stomach bleeding.Fatigue was the most common AE,followed by hypertension and elevated aminotransferase levels.Retrospective analysis for PDL1 expression revealed that PDL1 positive tumor cells were associated with improved clinical benefits and survival outcomes.Conclusions:LEP is a promising alternative as a non-first-line therapeutic regimen for patients with refractory BTC.Furthermore,well-designed prospective clinical trials with a control arm are still needed to obtain more evidences to confirm the efficacy and safety of this particular regimen as well as the role of PDL1 expression.

Mutation profile and its correlation with clinicopathology in Chinese hepatocellular carcinoma patients

Background:Hepatocellular carcinoma(HCC)is one of the most common causes of cancer worldwide.Although many studies have focused on oncogene characteristics,the genomic landscape of Chinese HCC patients has not been fully clarified.Methods:A total of 165 HCC patients,including 146 males and 19 females,were enrolled.The median age was 55 years(range,27-78 years).Corresponding clinical and pathological information was collected for further analysis.A total of 168 tumor tissues from these patients were selected for next-generation sequencing(NGS)-based 450 panel gene sequencing.Genomic alterations including single nucleotide variations(SNV),short and long insertions and deletions(InDels),copy number variations,and gene rearrangements were analyzed.Tumor mutational burden(TMB)was measured by an algorithm developed in-house.The top quartile of HCC was classified as TMB high.Results:A total of 1,004 genomic alterations were detected from 258 genes in 168 HCC tissues.TMB values were identified in 160 HCC specimens,with a median TMB of 5.4 Muts/Mb(range,0-28.4 Muts/Mb)and a 75%TMB of 7.7 Muts/Mb.The most commonly mutated genes were TP53,TERT,CTNNB1,AXIN1,RB1,TSC2,CCND1,ARID1A,and FGF19.SNV was the most common mutation type and C:G>T:A and guanine transformation were the most common SNVs.Compared to wild-type patients,the proportion of Edmondson grade III-IV and microvascular invasion was significantly higher in TP53 mutated patients(P<0.05).The proportion of tumors invading the hepatic capsule was significantly higher in TERT mutated patients(P<0.05).The proportion of Edmondson grade I-II,alpha fetoprotein(AFP)<25μmg/L,and those without a history of hepatitis B was significantly higher in CTNNB1 mutated patients(P<0.05).CTNNB1 mutations were associated with TMB high in HCC patients(P<0.05).Based on correlation analysis,the mutation of TP53 was independently correlated with microvascular invasion(P=0.002,OR=3.096)and Edmondson grade III-IV(P=0.008,OR=2.613).The mutation of TERT was independently correlated with tumor invasion of the liver capsule(P=0.001,OR=3.030),and the mutation of CTNNB1 was independently correlated with AFP(<25μmg/L)(P=0.009,OR=3.414).Conclusions:The most frequently mutated genes of HCC patients in China were TP53,TERT,and CTNNB1,which mainly lead to the occurrence and development of HCC by regulating the P53 pathway,Wnt pathway,and telomere repair pathway.There were more patients with microvascular invasion and Edmondson III-IV grade in TP53 mutated patients and more patients with hepatic capsule invasion in TERT mutated patients,while in CTNNB1 mutated patients,there were more patients with Edmondson I-II grade,AFP<25μmg/L,and a non-hepatitis B background.Also,the TMB values were significantly higher in CTNNB1 mutated patients than in wild type patients.

Toripalimab in advanced biliary tract cancer

Gemcitabine combined with platinum/fluorouracil drugs is the standard firstline treatment for advanced biliary tract cancers(BTCs).We explored the safety and efficacy of toripalimab plus gemcitabine and S-1(GS)as the first-line treatment for advanced BTCs.At a one-sided significance level of 0.025,a total of 50 patients could provide 80%power to show the efficacy at targeted progression-free survival(PFS)rate at 6 months of 70%versus 40%for the combined treatment.This single-arm,phase II study enrolled 50 patients with advanced BTCs who previously received no systemic treatment.The regimen was as follows:toripalimab(240 mg,i.v.,d1),gemcitabine(1,000 mg/m2,i.v.,d1 and d8),and S-1(40–60 mg bid p.o.,d1–14,Q21d).The primary endpoint was progression-free survival.The secondary endpoints included overall survival(OS),objective response rate(ORR),duration of response(DOR),and safety.The associations between response with PDL1 expression,tumor mutational burden(TMB),and genetic variations were explored.Patients were enrolled from January 2019 to August 2020,with a median follow-up time of 24.0 months(IQR:4.3–31.0 months).

Comprehensive molecular profiling of extrahepatic cholangiocarcinoma in Chinese population and potential targets for clinical practice

Background:Cholangiocarcinoma(CCA)is a diverse group of malignancies arising from the intra-or extrahepatic biliary epithelium and characterized by its late diagnosis and fatal outcome.Extrahepatic cholangiocarcinoma(ECC)accounts for 90%of CCA.However,little is known about the comprehensive genomic alterations of ECC in Chinese population for providing clinical managements especially targeted therapy.Methods:Comprehensive genomic profiling(CGP)was performed with next generation sequencing panel on paraffin-embedded tumor from a cohort of 80 Chinese ECC patients.Results:The most frequently altered genes were TP53(68%),KRAS(46%),SMAD4(22%),ARID1A(20%)and CDKN2A(19%).Mutual exclusivity was observed between multiple genes including ARID1A:TP53,KRAS:LRP1B and NF2:TP53.Genetic alterations with potential therapeutic implications were identified in 43%of patients.The top three actionable alterations include CDKN2A(n=11),BRAF(n=5)and ERBB2(n=4).Potentially actionable alterations were mainly enriched in the G1-S transition,homologous recombination repair,MAPK/ERK pathway.Conclusions:This is the largest data set of ECC cases providing a comprehensive view on genetic alterations in Chinese population which differs significantly from a US cohort,and indicates the potential clinical implications for targeted therapies.

Somatic genetic aberrations in gallbladder cancer: comparison between Chinese and US patients

Background:Gallbladder cancer(GBC)is often diagnosed at an advanced stage with limited therapeutic options and poor prognosis.The five-year survival rate of this cancer when diagnosed at an advanced stage is below 5%,and the median survival time is less than a year with standard gemcitabine-based chemotherapy.Survival benefit with second-line treatment is unknown.Thus,there is an urgent need for novel treatment strategies and targeted therapy based on next generation sequencing(NGS)may be of value.Methods:Comprehensive genomic profiling(CGP)was performed with NGS panel on paraffin-embedded tumors from a cohort of 108 Chinese and 107 US GBC patients.Clinical data were collected using an IRB approved protocol from a single-center in US and from China.Results:In Chinese and US GBC cohorts,an average of 6.4 vs.3.8 genomic alterations(GAs)were identified per patient.The most frequent alterations were TP53(69.4%),CDKN2A/B(26%),ERBB2(18.5%),PIK3CA(17%)and CCNE1(13%)in Chinese cohort,TP53(57.9%),CDKN2A/B(25%),SMAD4(17%),ARID1A(14%),PIK3CA(14%)and ERBB2(13.1%)in US patients.NFE2L2 mutations were present in 6.5%of Chinese patients and not observed in the US cohort.Interestingly,ERBB2 genetic aberrations were significantly associated with better pathological tumor differentiation and tended to co-occurrence with CDKN2A/B mutations in both the Chinese and US GBC cases.Out of the top 9 dysregulated genetic pathways in cancer,Chinese patients harbored more frequent mutations in ERBB genes(30.6%vs.19.0%,P=0.04).High frequency of PI3K/mTOR pathway variations was observed in both Chinese(37%)and US cohort(33%)(P=0.5).Additionally,both Chinese and US GBC patients exhibited a relatively high tumor mutational burden(TMB)(17.6%and 17.0%,respectively).In the Chinese cohort,a significant association was seen between direct repair gene alterations and TMB≥10 muts/Mb(P=0.004).Conclusions:In our study,over 83%Chinese and 68%US GBC patients had actionable alterations that could potentially guide and influence personalized treatment options.The identification of high TMB,ERBB2,CDKN2A/B,PI3K/mTOR pathway and DNA repair mutations indicated that both Chinese and US GBC patients may benefit from targeted or immune checkpoint inhibitors.

Gefitinib(an EGFR tyrosine kinase inhibitor)plus anlotinib(an multikinase inhibitor)for untreated,EGFR-mutated,advanced non-small cell lung cancer(FL-ALTER):a multicenter phase III trial

Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor(EGFR)signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy.In this phase 3 study(ClinicalTrial.gov:NCT04028778),315 patients with treatment-naïve,EGFR-mutated,advanced non-small cell lung cancer(NSCLC)were randomized(1:1)to receive anlotinib or placebo plus gefitinib once daily on days 1–14 per a 3-week cycle.At the prespecified final analysis of progression-free survival(PFS),a significant improvement in PFS was observed for the anlotinib arm over the placebo arm(hazards ratio[HR]=0.64,95%CI,0.48–0.80,P=0.003).Particularly,patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib.The incidence of grade 3 or higher treatment-emergent adverse events was 49.7%of the patients receiving gefitinib plus anlotinib versus 31.0%of the patients receiving gefitinib plus placebo.Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve,EGFR-mutated,advanced NSCLC,with a manageable safety profile.

Expert consensus on the diagnosis and treatment of solid tumors with BRAF mutations

The BRAF gene is an important signaling molecule in human cells that is involved in the regulation of cell growth,differentiation,and survival.When the BRAF gene mutates,it can lead to abnormal activation of the signaling pathway,which promotes cell proliferation,inhibits cell apoptosis,and ultimately contributes to the occurrence and development of cancer.BRAF mutations are widely present in various cancers,including malignant melanoma,thyroid cancer,colorectal cancer,non-small cell lung cancer,and hairy cell leukemia,among others.BRAF is an important target for the treatment of various solid tumors,and targeted combination therapies,represented by BRAF inhibitors,have become one of the main treatment modalities for a variety of BRAF-mutation-positive solid tumors.