Impact of baseline steroids on the efficacy of neoadjuvant immunochemotherapy in locally advanced esophageal squamous cell carcinoma

BACKGROUND Immunochemotherapy involving the combination of programmed cell death 1/programmed cell death ligand 1 inhibitors with chemotherapy has advanced the treatment of locally advanced esophageal squamous cell carcinoma(ESCC).The use of corticosteroids as pretreatment might reduce immunotherapy efficacy.AIM To investigate the impact of baseline corticosteroid use on neoadjuvant immunochemotherapy(nIC)outcomes in locally advanced ESCC patients.METHODS Patients with locally advanced ESCC who received nIC at Sun Yat-sen University Cancer Center and the Third Affiliated Hospital of Sun Yat-sen University were included.Patients were divided into dexamethasone and antihistamine groups on the basis of the administered pretreatment.Antiallergic efficacy and safety were evaluated,as well as its impact on short-term efficacy[complete pathological response(pCR),major pathological response(MPR)]and long-term efficacy[overall survival(OS),progression-free survival(PFS)]of nIC.RESULTS From September 2019 to September 2023,142 patients were analyzed.No severe treatment-related adverse events or deaths were observed.Allergy occurrence was greater in the antihistamine group(P=0.014).Short-term efficacy was not significantly different:The pCR rates were 29.9%and 40.0%,and the MPR rates were 57.9%and 65.7%in the dexamethasone and antihistamine groups,respectively.The long-term efficacy was not significantly different:The 2 years OS rates were 95.2%and 93.5%,and the 2 years PFS rates were 90.3%and 87.8%.Subgroup analysis revealed no difference in OS between the 20 mg dexamethasone group and the<20 mg dexamethasone group,but PFS was significantly greater in the 20 mg dexamethasone group(93.9%vs 56.4%,P=0.001).CONCLUSION Dexamethasone or antihistamines can be used before nIC in locally advanced ESCC without affecting short-or long-term efficacy.Administering 20 mg dexamethasone before nIC may improve PFS in ESCC.

Methyl-methanesulfonate sensitivity 19 expression is associated with metastasis and chemoradiotherapy response in esophageal cancer

AIM: To investigate the clinical significance of methylmethanesulfonate sensitivity 19(MMS19) expression in esophageal squamous cell carcinoma(ESCC).METHODS: Between June 2008 and May 2013, specimens from 103 patients who underwent endoscopic biopsy for the diagnosis of ESCC at the endoscopy center of Sun Yat-Sen University Cancer Center were collected; 52 matched-normal esophageal squamous epithelium samples were biopsied as controls.MMS19 protein expression was measured by immunohistochemistry.Of the 103 cases of ESCC, 49 received radical surgery following neoadjuvant chemoradiotherapy consisting of concurrent radiation in a total dose of 40 Gy and two cycles of chemotherapy with vinorelbine and cisplatin.Relationships between MMS19 expression, clinicopathologic characteristics and chemoradiotherapy response were analyzed.RESULTS: The MMS19 protein could be detected in both the cytoplasm and nucleus of most specimens.High cytoplasmic expression of MMS19 was detected in 63.1% of ESCC samples, whereas high nuclearexpression of MMS19 was found in 35.0%.High cytoplasmic MMS19 expression was associated with regional lymph node metastases(OR = 11.3, 95%CI: 2.3-54.7; P < 0.001) and distant metastases(OR = 13.1, 95%CI: 1.7-103.0; P = 0.002).Furthermore, high cytoplasmic MMS19 expression was associated with a response of ESCC to chemoradiotherapy(OR = 11.5, 95%CI: 3.0-44.5; P < 0.001), with a high cytoplasmic MMS19 expression rates in 79.3% and 25.0% of patients from the good chemoradiotherapy response group and poor response group, respectively.Nuclear MMS19 expression did not show any significant association with clinicopathologic characteristics or chemoradiotherapy response in ESCC.CONCLUSION: The results of our preliminary study suggest that MMS19 may be a potential new predictor of metastasis and chemoradiotherapy response in ESCC.

Evaluation of preoperative staging for esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma(ESCC) is known for its rapid progression and poor outcomes. China has the highest incidence and mortality in the world. Diagnoses made at early stages and accurate staging are associated with better outcomes, all of which can play a significant role in the selection of treatment protocols. ESCC is staged according to the widely accepted TNM system. Common imaging modalities used in staging ESCC before treatment include endoscopy, computed tomography(CT), positron emission tomography(PET) and magnetic resonance imaging(MRI). Endoscopic ultrasound is useful for staging tumor depth and nodal status. Narrow band imaging is valuable for early stage disease assessment. CT and PET provide additional valuable information regarding node and metastasis staging. The ability of MRI to delineate ESCC is continuously being improved and adds information regarding locoregional status to routine examinations.

Prognostic role of neutrophil-lymphocyte ratio in operable esophageal squamous cell carcinoma

AIM:To explore the relationship of clinicopathological features and the distribution of neutrophils in the t umor mic roenvironment wi t h t he prognosis of cholangiocarcinoma.METHODS:Two hundred and fifty-four formalin-fixed and paraffin embedded tissue blocks were analyzed, including tissues from cholangiocarcinoma(n = 254), and tumor adjacent tissues(n = 238).Tissue sections were stained for CD15 using immunohistochemical staining.CD15 expression was detected to identify the distribution of neutrophils in the local tumor microenvironment.The neutrophil density of the tumor tissues and the adjacent tumor tissues was detected to reflect their inflammatory status.Clinical data and follow-up information of cholangiocarcinoma patients who underwent surgery from January 2004 to December 2010 were analyzed retrospectively.The relationship between clinicopathological features and the distribution of neutrophils with prognosis of the patients were analyzed.RESULTS:The positive expression level of CD15 was only significantly related to the TNM stage.CD15 expression was higher in tumor tissues than in adjacent tissues(73.6% vs 54.6%), with significant differences.Patients with high expression of CD15 had significantly shorter overall survival(OS) than those with low expression of CD15(median overall survival time 39.77 mo vs 16.87 mo, P = 0.008).Patients with high CD15 expression had significantly shorter disease free survival time(DFS) than those with low expression of CD15(median DFS 38.27 mo vs 16.83 mo, P = 0.029).COX multivariate analysis indicated that high CD15 expression in tumor tissues was an independent risk factor for predicting OS for patients with cholangiocarcinoma [P = 0.012, relative risk(RR) = 1.601], but it was not an independent risk factor for predicting DFS(P = 0.073, RR = 1.462).CONCLUSION:Patients with high CD15 expression in cancer tissues had shorter DFS and OS.High expression of CD15 is an independent risk factor for OS.

Endoscopic ultrasonography for staging of T1a and T1b esophageal squamous cell carcinoma

AIM: To investigate the accuracy of Endoscopic ultrasound (EUS) in staging and sub-staging T1a and T1b esophageal squamous cell carcinoma (ESCC).

Concurrent chemoradiotherapy combined with enteral nutrition support:a radical treatment strategy for esophageal squamous cell carcinoma patients with malignant istulae

Background: Concurrent chemoradiotherapy(CCRT) significantly increases the survival rate of esophageal squa?mous cell carcinoma(ESCC) patients with malignant fistulae. Recent clinical evidence has shown the benefits of enteral nutrition for malnourished cancer patients. In this study, we aimed to validate that, with the support of enteral nutrition, ESCC patients who develop malignant fistulae might be able to complete CCRT and achieve long?term survival.Methods: We reviewed the medical records of 652 patients with ESCC who received definitive CCRT at Sun Yat?sen University Cancer Center between January 2010 and December 2012. Treatment outcome and toxicity were ret?rospectively evaluated in 40 ESCC patients with malignant fistulae. All the 40 patients were treated with CCRT and evaluated by clinical nutritionists using nutrition risk screening(NRS) before, during, and after treatment. Twenty?two patients received a nasogastric tube, and 18 underwent percutaneous endoscopic gastrostomy feeding. The median energy intake was 2166 kcal/day. Treatment response was evaluated at 3 months after the completion of CCRT.Results: With a median follow?up of 18 months(range, 3–39 months), patients' 1?year overall survival(OS) rate was 62.5%, and the estimated OS time was 25.5 months. Univariate analysis showed that the NRS score(P n NRS score(P se to treatment(P < 0.001) were sig= 0.003), increase i= 0.024), fistula closure(P = 0.011), and responnifi?cantly associated with OS. Multivariate analysis showed that tumor response(P = 0.044) and increase in NRS score(P = 0.044) were independent predictors of OS. Grade 3 vomiting was observed in 8 patients(20.0%), grade 3 neutro?penia was observed in 11 patients(27.5%), and grade 3 cough was observed in 13 patients(32.5%); 2 patients(5.0%) died of massive bleeding during treatment.Conclusions: CCRT combined with enteral nutrition support is effective for ESCC patients with malignant fistulae. Patients have an increased potential to be cured, especially those who experience complete response and have an increase in NRS score. Careful observation and nutrition support are required for patients with advanced T?category ESCC who undergo CCRT.

Maximum standardized uptake value on PET/CT in preoperative assessment of lymph node metastasis from thoracic esophageal squamous cell carcinoma

The presence of lymph node metastasis is an important prognostic factor for patients with esophageal cancer.Accurate assessment of lymph nodes in thoracic esophageal carcinoma is essential for selecting appropriate treatment and forecasting disease progression.Positron emission tomography combined with computed tomography(PET/CT)is becoming an important tool in the workup of esophageal carcinoma.Here,we evaluated the effectiveness of the maximum standardized uptake value(SUVmax)in assessing lymph node metastasis in esophageal squamous cell carcinoma(ESCC)prior to surgery.Fifty-nine surgical patients with pathologically confirmed thoracic ESCC were retrospectively studied.These patients underwent radical esophagectomy with pathologic evaluation of lymph nodes.They all had18F-FDG PET/CT scans in their preoperative staging procedures.None had a prior history of cancer.The pathologic status and PET/CT SUVmax of lymph nodes were collected to calculate the receiver operating characteristic(ROC)curve and to determine the best cutoff value of the PET/CT SUVmax to distinguish benign from malignant lymph nodes.Lymph node data from 27 others were used for the validation.A total of 323 lymph nodes including 39 metastatic lymph nodes were evaluated in the training cohort,and 117lymph nodes including 32 metastatic lymph nodes were evaluated in the validation cohort.The cutoff point of the SUVmax for lymph nodes was 4.1,as calculated by ROC curve(sensitivity,80%;specificity,92%;accuracy,90%).When this cutoff value was applied to the validation cohort,a sensitivity,a specificity,and an accuracy of 81%,88%,and 86%,respectively,were obtained.These results suggest that the SUVmax of lymph nodes predicts malignancy.Indeed,when an SUVmax of 4.1 was used instead of 2.5,FDG-PET/CT was more accurate in assessing nodal metastasis.

Aggressive surgical resection does not improve survival in operable esophageal squamous cell carcinoma with N2-3 status

AIM:To investigate the influence of nodal status on response and clarify the optimal treatment for operable esophageal squamous cell carcinoma(OSCC).METHODS:We retrospectively analyzed 1490 OSCC patients who underwent transthoracic esophagectomy and lymphadenectomy between December 1996 and December 2009 at the Sun Yat-sen University Cancer Center.The surgical approach and the number of resected lymph nodes(LNs) were considered in the assessment of surgery.Patients were classified according to their nodal statuses(NO vs N1 vs N2-3).Overall survival was defined as the time from the date of death or final follow-up.Survival analysis was performed using the Kaplan-Meier method and differences between curves were assessed by the logrank test.Univariate and multivariate Cox regression analyses were used to identify factors associated with prognosis.Statistical significance was assumed at a P<0.05.RESULTS:With a median time from surgery to the last censoring date for the entire cohort of 72.2 mo,a total of 631 patients were still alive at the last follow-up and the median survival time was 35.5 mo.The surgical approach(left transthoracic vs Ivor-Lewis/tri-incisional)was verified as independent prognostic significance in patients with NO or N1 status,but not in those with N2-3 status.Similar results were also observed with the number of resected LNs(≤14 vs ≥15).Compared with surgery alone,combined therapy achieved better outcomes in patients with N1 or N2-3 status,but not in those with NO status.For those with N2-3status,neither the surgical approach nor the number of resected LNs reached significance by univariate analysis,with unadjusted HRs of 0.826(95%CI:0.644-1.058) and 0.849(95%CI:0.668-1.078),respectively,and aggressiveness of surgery did not influence the outcome;the longest survival was observed in those patients who received the combined therapy.CONCLUSION:Combined therapy has a positive role in OSCC with LN metastasis,and aggressive surgical resection does not improve survival in patients with N2-3 status.

Prognostic values of apoptosis-stimulating P53-binding protein 1 and 2 and their relationships with clinical characteristics of esophageal squamous cell carcinoma patients:a retrospective study

Background: Esophageal squamous cell carcinoma(ESCC) is a leading cause of cancer?related death, and new prognostic biomarkers are urgently needed. Apoptosis?stimulating P53?binding protein 1(ASPP1) and 2(ASPP2) have been reported to play important roles in the development, progression, metastasis, and prognosis of cancers, but their roles in ESCC have not been elucidated. In this study, we examined the expression of ASPP1 and ASPP2 in ESCC to evaluate their prognostic values.Methods: The protein expression of ASPP1, ASPP2, and P53 in 175 specimens of ESCC was detected using immuno?histochemical staining; their expression in cancerous and noncancerous tissues was scored according to the stain?ing intensity and the percentage of stained cells. The associations of ASPP1, ASPP2, and P53 with clinicopathologic parameters, overall survival(OS), and disease?free survival(DFS) were analyzed.Results: The protein expression levels of ASPP2 and P53 were significantly higher in cancerous tissues than in paired noncancerous tissues(P < 0.001), whereas the expression levels of ASPP1 in the two groups were similar. In ESCCs, ASPP1 expression was significantly associated with histological differentiation(P = 0.002) and invasive depth(P = 0.014); ASPP2 expression was associated with age(P = 0.029) and histological differentiation(P < 0.001); and P53 expression was associated with age(P and P53 expression. Survival an= 0.021) and tumor size(P alysis revealed that high AS= 0.040). No correlations were found between ASPP1, ASPP2,PP2 expression was significantly associated with increased 5?year OS(P = 0.001) and DFS rates(P ate of ESCC patients(= 0.010) and that high P53 expression was significantly associated with a reduced 5?year DFS rP atio(HR): 0.541, 9= 0.015). Multivariate Cox analysis indicated that ASPP2 was an inde?pendent predictor of OS [hazard r5% confidence interval(CI) 0.363–0.804] and DFS(HR: 0.599, 95% CI 0.404–0.888) of ESCC patients and that P53 was an independent predictor of DFS(HR: 2.161, 95% CI 1.100–4.245).Conclusions: ASPP1 might be involved in the progression of ESCC, and ASPP2 was a potential prognostic biomarker of ESCC and should be evaluated in future studies.

Synthetic lethal short hairpin RNA screening reveals that ring finger protein 183 confers resistance to trametinib in colorectal cancer cells

Background: The mitogen-activated extracellular signal-regulated kinase 1/2(MEK1/2) inhibitor trametinib has shown promising therapeutic effects on melanoma, but its efficacy on colorectal cancer(CRC) is limited. Synthetic lethality arises with a combination of two or more separate gene mutations that causes cell death, whereas individual mutations keep cells alive. This study aimed to identify the genes responsible for resistance to trametinib in CRC cells,using a synthetic lethal short hairpin RNA(shRNA) screening approach.Methods: We infected HT29 cells with a pooled lentiviral shRNA library and applied next-generation sequencing to identify shRNAs with reduced abundance after 8-day treatment of 20 nmol/L trametinib. HCT116 and HT29 cells were used in validation studies. Stable ring finger protein 183(RNF183)-overexpressing cell lines were generated by pcDNA4-myc/his-RNF183 transfection. Stable RNF 183-knockdown cell lines were generated by infection of lentiviruses that express RNF183 shRNA, and small interference RNA(siRNA) was used to knock down RNF183 transiently.Quantitative real-time PCR was used to determine the mRNA expression. Western blotting, immunohistochemical analysis, and enzyme-linked immunosorbent assay(ELISA) were used to evaluate the protein abundance. MTT assay,colony formation assay, and subcutaneous xenograft tumor growth model were used to evaluate cell proliferation.Results: In the primary screening, we found that the abundance of RNF183 shRNA was markedly reduced after treatment with trametinib. Trametinib induced the expression of RNF183, which conferred resistance to drug-induced cell growth repression and apoptotic and non-apoptotic cell deaths. Moreover, interleukin-8(IL-8) was a downstream gene of RNF183 and was required for the function of RNF183 in facilitating cell growth. Additionally, elevated RNF183 expression partly reduced the inhibitory effect of trametinib on IL-8 expression. Finally, xenograft tumor model showed the synergism of RNF183 knockdown and trametinib in repressing the growth of CRC cells in vivo.Conclusion: The RNF183-IL-8 axis is responsible for the resistance of CRC cells to the MEK1/2 inhibitor trametinib and may serve as a candidate target for combined therapy for CRC.

Caspase-3 expression in metastatic lymph nodes of esophageal squamous cell carcinoma is prognostic of survival

AIM: To assess whether differential expression of caspase-3 in paired metastatic lymph nodes (LNs) is prognostic of survival in patients with resectable esophageal squamous cell carcinoma (ESCC).

Fibrin sealant for esophageal anastomosis:A phase II study

BACKGROUND Esophagectomy is a pivotal curative modality for localized esophageal or esophagogastric junction cancer(EC or EJC).Postoperative anastomotic leakage(AL)remains problematic.The use of fibrin sealant(FS)may improve the strength of esophageal anastomosis and reduce the incidence of AL.AIM To assess the efficacy and safety of applying FS to prevent AL in patients with EC or EJC.METHODS In this single-arm,phase II trial(Clinicaltrial.gov identifier:NCT03529266),we recruited patients aged 18-80 years with resectable EC or EJC clinically staged as T1-4aN0-3M0.An open or minimally invasive McKeown esophagectomy was performed with a circular stapled anastomosis.After performing the anastomosis,2.5 mL of porcine FS was applied circumferentially.The primary endpoint was the proportion of patients with AL within 3 mo.RESULTS From June 4,2018,to December 29,2018,57 patients were enrolled.At the data cutoff date(June 30,2019),three(5.3%)of the 57 patients had developed AL,including two(3.5%)with esophagogastric AL and one(1.8%)with gastric fistula.The incidence of anastomotic stricture and other major postoperative complications was 1.8%and 17.5%,respectively.The median time needed to resume oral feeding after operation was 8 d(Interquartile range:7.0-9.0 d).No adverse events related to FS were recorded.No deaths occurred within 90 d after surgery.CONCLUSION Perioperative sealing with porcine FS appears safe and may prevent AL after esophagectomy in patients with resectable EC or EJC.Further phase III studies are warranted.

Extraesophageal saline enhances endoscopic ultrasonography to differentiate esophagus and adjacent organs

AIM: To distinguish between the esophagus and adjacent organs using extraesophageal saline injection (ESI) in a canine model.

EFNA1 in gastrointestinal cancer:Expression,regulation and clinical significance

Ephrin-A1 is a protein that in humans is encoded by the EFNA1 gene.The ephrins and EPH-related receptors comprise the largest subfamily of receptor proteintyrosine kinases which play an indispensable role in normal growth and development or in the pathophysiology of various tumors.The role of EFNA1 in tumorigenesis and development is complex and depends on the cell type and microenvironment which in turn affect the expression of EFNA1.This article reviews the expression,prognostic value,regulation and clinical significance of EFNA1 in gastrointestinal tumors.

Small-molecule agents for cancer immunotherapy

Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regression and overall survival benefit in many types of cancer.With the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for immunotherapy.Small molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively investigated.Monotherapy of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance.Here,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

Fibrin sealant for the prevention of anastomotic leakage after esophagectomy for esophageal or esophagogastric junction cancer:interim report of a prospective,phase III,randomized controlled study

Purpose Anastomotic leakage(AL)is one of the most pernicious complications after esophagectomy for patients with esophageal or esophagogastric junction cancer(EC or EJC).The application of fibrin sealant(FS)may be advantageous for reducing the incidence of AL.This study aims to evaluate the safety and effectiveness of FS in preventing AL in patients undergoing McKeown esophagectomy.Methods In this multicenter,prospective,randomized controlled trial,we planned to recruit 360 patients aged 18–75 years with resectable EC or EJC and the interim analysis was performed when the number of participants reaches 180.Patients assigned to the FS group received McKeown esophagectomy with 2.5ml FS applied to the cervical anastomosis,while patients in the control group received surgery alone.The primary endpoint was the incidence of cervical AL within the first 3 months postoperatively.Result From February 2019 to November 2021,180 patients were recruited,with 89 in the FS group and 91 in the control group.There was no statistically difference between the incidence of AL between the two groups[6.7%(6/89)in the FS vs.14.3%(13/91)in the control group,P=0.16].Complications was comparable(P=0.76)between the FS group(42 of 89,47.2%)and the control group(45 of 91,49.5%).No adverse events related to FS or deaths occurred postoperatively.Conclusion The application of FS intraoperatively is feasible and does not increase the risk of complications,and its effectiveness for the prevention of AL needs to be revalidated after the completion of patient enrollment.Trial registration This trial was registered at ClinicalTrials.gov(NCT03847857)on February 19th,2019.

A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block “eat-me” signal

Immune checkpoint inhibitors(ICIs)have induced durable clinical responses in a subset of patients with colorectal cancer(CRC).However,the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge to current immunotherapies.Inflammation-related molecule A20 is closely related to cancer immune response,but the effect of A20 on“eat-me”signal and immunotherapy efficacy remains elusive.We found that A20 downregulation prominently improved the antitumor immune response and the efficacy of PD-1 inhibitor in CRC in vitro and in vivo.Higher A20 expression was associated with less infiltration of immune cells including CD3(+),CD8(+)T cells and macrophages in CRC tissues and also poorer prognosis.Gain-and loss-A20 functional studies proved that A20 could decrease the“eat-me”signal calreticulin(CRT)protein on cell membrane translocation via upregulating stanniocalcin 1(STC1),binding to CRT and detaining in mitochondria.Mechanistically,A20 inhibited GSK3βphosphorylating STC1 at Thr86 to slow down the degradation of STC1 protein.Our findings reveal a new crosstalk between inflammatory molecule A20 and“eat-me”signal in CRC,which may represent a novel predictive biomarker for selecting CRC patients most likely to benefit from ICI therapy.

The role of ALDH2 in tumorigenesis and tumor progression:Targeting ALDH2 as a potential cancer treatment

A major mitochondrial enzyme for protecting cells from acetaldehyde toxicity is aldehyde dehydrogenase 2(ALDH2).The correlation between ALDH2 dysfunction and tumorigenesis/growth/metastasis has been widely reported.Either low or high ALDH2 expression contributes to tumor progression and varies among different tumor types.Furthermore,the ALDH2*2 polymorphism(rs671) is the most common single nucleotide polymorphism(SNP) in Asia.Epidemiological studies associate ALDH2*2 with tumorigenesis and progression.This study summarizes the essential functions and potential ALDH2 mechanisms in the occurrence,progression,and treatment of tumors in various types of cancer.Our study indicates that ALDH2 is a potential therapeutic target for cancer therapy.

KRAS mutation:from undruggable to druggable in cancer

Cancer is the leading cause of death worldwide,and its treatment and outcomes have been dramatically revolutionised by targeted therapies.As the most frequently mutated oncogene,Kirsten rat sarcoma viral oncogene homologue(KRAS)has attracted substantial attention.The understanding of KRAS is constantly being updated by numerous studies on KRAS in the initiation and progression of cancer diseases.However,KRAS has been deemed a challenging therapeutic target,even“undruggable”,after drugtargeting efforts over the past four decades.Recently,there have been surprising advances in directly targeted drugs for KRAS,especially in KRAS(G12C)inhibitors,such as AMG510(sotorasib)and MRTX849(adagrasib),which have obtained encouraging results in clinical trials.Excitingly,AMG510 was the first drug-targeting KRAS(G12C)to be approved for clinical use this year.This review summarises the most recent understanding of fundamental aspects of KRAS,the relationship between the KRAS mutations and tumour immune evasion,and new progress in targeting KRAS,particularly KRAS(G12C).Moreover,the possible mechanisms of resistance to KRAS(G12C)inhibitors and possible combination therapies are summarised,with a view to providing the best regimen for individualised treatment with KRAS(G12C)inhibitors and achieving truly precise treatment.

Secalonic acid D induces cell apoptosis in both sensitive and ABCG2-overexpressing multidrug resistant cancer cells through upregulating c-Jun expression

Secalonic acid D(SAD) could inhibit cell growth in not only sensitive cells but also multidrug resistant(MDR) cells. However, the molecular mechanisms need to be elucidated. Here, we identified that SAD possessed potent cytotoxicity in 3 pairs of MDR and their parental sensitive cells including S1-MI-80 and S1,H460/MX20 and H460, MCF-7/ADR and MCF-7 cells. Furthermore, SAD induced cell G2/M phase arrest via the downregulation of cyclin B1 and the increase of CDC2 phosphorylation. Importantly, JNK pathway upregulated the expression of c-Jun in protein level and increased c-Jun phosphorylation induced by SAD, which was linked to cell apoptosis via c-Jun/Src/STAT3 pathway. To investigate the mechanisms of upregulation of c-Jun protein by SAD, the mR NA expression level and degradation of c-Jun were examined. We found that SAD did not alter the mR NA level of c-Jun but inhibited its proteasome-dependent degradation. Taken together, these results implicate that SAD induces cancer cell death through c-Jun/Src/STAT3 signaling axis by inhibiting the proteasome-dependent degradation of c-Jun in both sensitive cells and ATP-binding cassette transporter sub-family G member 2(ABCG2)-mediated MDR cells.