The miR‐200 family differentially regulates sensitivity to paclitaxel and carboplatin in human ovarian carcinoma OVCAR‐3 and MES‐OV cells

We studied the role of miRNA‐200 family members in cellular sensitivity to paclitaxel and carboplatin, using two ovarian cancer cell lines, OVCAR‐3 and MES‐OV, and their paclitaxel resistant variants OVCAR‐3/TP and MES‐OV/TP. Both resistant variants display a strong epithelial‐mesenchymal transition (EMT) phenotype, with marked decreases in expression of miR‐200c and miR‐141 in OVCAR‐3/TP, and down‐regulation of all five members of the miR‐200 family in MES‐OV/TP. Lentiviral transfection of inhibitors of miR‐200c or miR‐141 in parental OVCAR‐3 triggered EMT and rendered the cells resistant to paclitaxel and carboplatin. Conversely, the infection of OVCAR‐3/TP cells with retroviral particles carrying the miR‐200ab429 and 200c141 clusters triggered a partial mesenchymal to epithelial transition (MET). This partial MET was not sufficient to re‐sensitize OVCAR‐3/TP cells to paclitaxel. However, the miR‐200c/miR‐141 cluster transfectants became 6–8x resistant to carboplatin, an unexpected result, whereas miR‐200a/miR‐200b/miR‐429 had no effect. Transfecting the OVCAR‐3/TP GFP cells with specific miRNA mimics confirmed these data. MiR‐200c and miR‐141 mimics conferred resistance to carboplatin in MES‐OV/TP cells, similar to OVCAR‐3/TP, but sensitized MES‐OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR‐3/TP 200c141 cells compared to controls. The miR‐200 family plays major, cell‐context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR‐3 and MES‐OV cells.     

Sortilin‐related receptor is a druggable therapeutic target in breast cancer

In breast cancer, the currently approved anti‐receptor tyrosine‐protein kinase erbB‐2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2‐related therapeutic targets could offer a means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin‐related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2‐targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti‐SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumab in vitro and in ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cell density in a mouse xenograft model of HER2‐positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient‐derived explant three‐dimensional cultures. These results provide, for the first time, proof of principle that SorLA is a druggable target in breast cancer.     

Enhanced anti‐tumor effects of the PD‐1 blockade combined with a highly absorptive form of curcumin targeting STAT3

PD‐1/PD‐L1 immune checkpoint inhibitors are promising cancer immunotherapies however responses are still limited and the development of more effective combination immunotherapy is needed. We previously reported that STAT3 activation in cancer cells and immune cells was involved in immune‐resistant mechanisms. In this study, we evaluated the effect of highly absorptive forms of curcumin extracts and synthetic curcumin on anti‐tumor T cell responses. The curcumin po administration resulted in the significant augmentation of in vivo induction of tumor antigen‐specific T cells through restoration of dendritic cells (DCs) by inhibiting directly STAT3 in DCs and indirectly via reduced IL‐6 production from STAT3 activated cancer cells in 2 syngeneic MC38 and CT26 murine tumor models. Curcumin also showed direct DC enhancing activity and enhanced T cell induction for the immunized antigens in non‐tumor‐bearing mice and human hosts. Curcumin restored DC functions in xenogeneic nude mouse model implanted with high IL‐6‐producing human clear cell ovarian cancer cells. The combination of curcumin and PD‐1/PD‐L1 Abs demonstrated a synergistic anti‐tumor activity in MC38 murine tumor models. These results indicated that curcumin augments the induction of tumor antigen‐specific T cells by restoring the T cell stimulatory activity of DCs targeting activated STAT3 in both cancer cells and immune cells. Combination immunotherapy with curcumin and PD‐1/PD‐L1 Ab is an attractive strategy in the development of effective immunotherapy against various cancers.     

BRCA2 inhibition enhances cisplatin‐mediated alterations in tumor cell proliferation,metabolism, and metastasis

Tumor cells have unstable genomes relative to non‐tumor cells. Decreased DNA integrity resulting from tumor cell instability is important in generating favorable therapeutic indices, and intact DNA repair mediates resistance to therapy. Targeting DNA repair to promote the action of anti‐cancer agents is therefore an attractive therapeutic strategy. BRCA2 is involved in homologous recombination repair. BRCA2 defects increase cancer risk but, paradoxically, cancer patients with BRCA2 mutations have better survival rates. We queried TCGA data and found that BRCA2 alterations led to increased survival in patients with ovarian and endometrial cancer. We developed a BRCA2‐targeting second‐generation antisense oligonucleotide (ASO), which sensitized human lung, ovarian, and breast cancer cells to cisplatin by as much as 60%. BRCA2 ASO treatment overcame acquired cisplatin resistance in head and neck cancer cells, but induced minimal cisplatin sensitivity in non‐tumor cells. BRCA2 ASO plus cisplatin reduced respiration as an early event preceding cell death, concurrent with increased glucose uptake without a difference in glycolysis. BRCA2 ASO and cisplatin decreased metastatic frequency in vivo by 77%. These results implicate BRCA2 as a regulator of metastatic frequency and cellular metabolic response following cisplatin treatment. BRCA2 ASO, in combination with cisplatin, is a potential therapeutic anti‐cancer agent.     

CCR9‐mediated signaling through β‐catenin and identification of a novel CCR9 antagonist

Elevated levels of chemokine receptor CCR9 expression in solid tumors may contribute to poor patient prognosis. In this study, we characterized a novel CCR9‐mediated pathway that promotes pancreatic cancer cell invasion and drug resistance, indicating that CCR9 may play a critical role in cancer progression through activation of β‐catenin. We noted that the CCL25/CCR9 axis in pancreatic cancer cells induced the activation of β‐catenin, which enhanced cell proliferation, invasion, and drug resistance. CCR9‐mediated activation of β‐catenin and the resulting downstream effects were effectively inhibited by blockade of the PI3K/AKT pathway, but not by antagonism of Wnt. Importantly, we discovered that CCR9/CCL25 increased the lethal dose of gemcitabine, suggesting decreased efficacy of anti‐cancer drugs with CCR9 signaling. Through in silico computational modeling, we identified candidate CCR9 antagonists and tested their effects on CCR9/β‐catenin regulation of cell signaling and drug sensitivity. When combined with gemcitabine, it resulted in synergistic cytotoxicity. Our results show that CCR9/β‐catenin signaling enhances pancreatic cancer invasiveness and chemoresistance, and may be a highly novel therapeutic target.     

Weekly Carboplatin and Paclitaxel: A Retrospective Comparison with the Three‐Weekly Schedule in First‐Line Treatment of Ovarian Cancer

BackgroundConventional first‐line combination therapy for ovarian cancer comprises 6 cycles of adjuvant or neoadjuvant carboplatin (AUC5‐6) with paclitaxel (175 mg/m²) every 3 weeks (PC‐3W). Weekly scheduling of paclitaxel may maximize its antiangiogenic effect and reduce adverse effects. We compared the efficacy and safety of PC‐3W with a modified protocol of weekly paclitaxel 80 mg/m² and weekly carboplatin AUC2 administered on days 1, 8, and 15 in a 28‐day cycle (i.e., with 1 week off‐treatment [PC‐W]).Materials and MethodsMedical records of consecutive patients treated between 2000 and 2018 were reviewed; 707 patients were analyzed for demographic and clinical characteristics, effectiveness and toxicity.ResultsPC‐3W was administered to 402 patients (median age, 60.5 years) and PC‐W to 305 patients (median age, 62.5 years). Most patients (91.4%) were diagnosed at stage III–IV. Notwithstanding a higher proportion of residual disease and older patients in the PC‐W group, median progression‐free survival was 21.4 months and 13.2 months for PC‐W and PC‐3W, respectively; median overall survival was 75.2 and 54.0 months for PC‐W and PC‐3W, respectively. Cox proportional hazards model indicated improved survival for patients treated with PC‐W (hazard ratio, 0.54). Similar results were observed for older patients diagnosed at ≥75 years. PC‐W demonstrated a better safety profile, with lower incidence of neuropathy, neutropenia, and alopecia.ConclusionPC‐W is as active and better tolerated than the standard PC‐3W regimen. PC‐W may serve as an alternative option for elderly or frail patients.Implications for PracticeWeekly scheduling of paclitaxel 80 mg/m² and carboplatin AUC2, administered on days 1, 8, and 15 in a 28‐day cycle (PC‐W) for first‐line therapy for advanced ovarian cancer, is as active and better tolerated than the standard regimen of carboplatin and paclitaxel (175 mg/m²) every 3 weeks (PC‐3W). It is possible that the weekly holiday on day 21 in the PC‐W regimen may ensure better completion rates (which may result in treatment delays for toxicity in PC‐3W). The results of this retrospective analysis highlight the weekly regimen as a valid treatment option, especially for elderly patients and those with significant comorbidities.     

pERK 1/2 inhibit Caspase‐8 induced apoptosis in cancer cells by phosphorylating it in a cell cycle specific manner

ERK 1/2 are found to be hyperactive in many cancers. Active ERK 1/2 (pERK 1/2) are known to protect cancer cells from undergoing death receptor‐mediated apoptosis, although the mechanism(s) behind this is poorly understood. Through in vitro kinase assays and mass‐spectrometry we demonstrate that pERK 1/2 can phosphorylate pro‐Caspase‐8 at S387. Also, in EGFR‐overexpressing Type I and II ovarian and breast cancer cell lines respectively, ERK 1/2 remain active only during the interphase. During this period, pERK 1/2 could inhibit Trail‐induced apoptosis, most effectively during the G1/S phase. By knocking‐down the endogenous pro‐Caspase‐8 using RNAi and replacing it with its non‐phosphorylatable counterpart (S387A), a significant increase in Caspase‐8 activity upon Trail stimulation was observed, even in the presence of pERK 1/2. Taken together, we propose that a combination of Trail and an inhibitor of ERK 1/2 activities could potentially enhance of Trail''s effectiveness as an anti‐cancer agent in ERK 1/2 hyperactive cancer cells.     

Recombinant nanobody against MUC1 tandem repeats inhibits growth,invasion, metastasis,and vascularization of spontaneous mouse mammary tumors

Alteration in glycosylation pattern of MUC1 mucin tandem repeats during carcinomas has been shown to negatively affect adhesive properties of malignant cells and enhance tumor invasiveness and metastasis. In addition, MUC1 overexpression is closely interrelated with angiogenesis, making it a great target for immunotherapy. Alongside, easier interaction of nanobodies (single‐domain antibodies) with their antigens, compared to conventional antibodies, is usually associated with superior desirable results. Herein, we evaluated the preclinical efficacy of a recombinant nanobody against MUC1 tandem repeats in suppressing tumor growth, angiogenesis, invasion, and metastasis. Expressed nanobody demonstrated specificity only toward MUC1‐overexpressing cancer cells and could internalize in cancer cell lines. The IC50 values (the concentration at which the nanobody exerted half of its maximal inhibitory effect) of the anti‐MUC1 nanobody against MUC1‐positive human cancer cell lines ranged from 1.2 to 14.3 nm. Similar concentrations could also effectively induce apoptosis in MUC1‐positive cancer cells but not in normal cells or MUC1‐negative human cancer cells. Immunohistochemical staining of spontaneously developed mouse breast tumors prior to in vivo studies confirmed cross‐reactivity of nanobody with mouse MUC1 despite large structural dissimilarities between mouse and human MUC1 tandem repeats. In vivo, a dose of 3 µg nanobody per gram of body weight in tumor‐bearing mice could attenuate tumor progression and suppress excessive circulating levels of IL‐1a, IL‐2, IL‐10, IL‐12, and IL‐17A pro‐inflammatory cytokines. Also, a significant decline in expression of Ki‐67, MMP9, and VEGFR2 biomarkers, as well as vasculogenesis, was evident in immunohistochemically stained tumor sections of anti‐MUC1 nanobody‐treated mice. In conclusion, the anti‐MUC1 tandem repeat nanobody of the present study could effectively overcome tumor growth, invasion, and metastasis.     

A novel anti‐c‐Kit antibody–drug conjugate to treat wild‐type and activating‐mutant c‐Kit‐positive tumors

c‐Kit overexpression and activating mutations, which are reported in various cancers, including gastrointestinal stromal tumor (GIST), small‐cell lung cancer (SCLC), acute myeloid leukemia, acral melanoma, and systemic mastocytosis (SM), confer resistance to tyrosine kinase inhibitors (TKIs). To overcome TKI resistance, an anti‐c‐Kit antibody–drug conjugate was developed in this study to treat wild‐type and mutant c‐Kit‐positive cancers. NN2101, a fully human IgG1, was conjugated to DM1, a microtubule inhibitor, through N‐succinimidyl‐4‐(N‐maleimidomethyl) cyclohexane‐1‐carboxylate (SMCC) (to give NN2101‐DM1). The antitumor activity of NN2101‐DM1 was evaluated in vitro and in vivo using various cancer cell lines. NN2101‐DM1 exhibited potent growth‐inhibitory activities against c‐Kit‐positive cancer cell lines. In a mouse xenograft model, NN2101‐DM1 exhibited potent growth‐inhibitory activities against imatinib‐resistant GIST and SM cells. In addition, NN2101‐DM1 exhibited a significantly higher anti‐cancer effect than carboplatin/etoposide against SCLC cells where c‐Kit does not mediate cancer pathogenesis. Furthermore, the combination of NN2101‐DM1 with imatinib in imatinib‐sensitive GIST cells induced complete remission compared with treatment with NN2101‐DM1 or imatinib alone in mouse xenograft models. These results suggest that NN2101‐DM1 is a potential therapeutic agent for wild‐type and mutant c‐Kit‐positive cancers.     

H1.0 induces paclitaxel‐resistance genes expression in ovarian cancer cells by recruiting GCN5 and androgen receptor

More than 90% of ovarian cancer deaths are due to relapse following development of chemoresistance. Our main objective is to better understand the molecular mechanism underlying paclitaxel resistance (taxol resistance, Txr) in ovarian cancer. Here, we observed that the linker histone H1.0 is upregulated in paclitaxel‐resistant ovarian cancer cells. Knockdown of H1.0 significantly downregulates the androgen receptor (AR) and sensitizes paclitaxel‐resistant SKOV3/Txr and 2774/Txr cell lines to paclitaxel. Conversely, ectopic expression of H1.0 upregulates AR and increases Txr in parental SKOV3 and MDAH2774 cells. Notably, H1.0 upregulation is associated with disease recurrence and poor survival in a subset of ovarian cancer subjects. Inhibition of PI3K significantly reduces H1.0 mRNA and protein levels in paclitaxel‐resistant cells, suggesting the involvement of the PI3K/AKT signaling pathway. Knockdown of H1.0 and AR also downregulates the Txr genes ABCB1 and ABCG2 in paclitaxel‐resistant cells. Our data show that H1.0 induces GCN5 expression and histone acetylation, thereby enhancing Txr gene transactivation. These findings suggest that Txr in ovarian cancer involves the PI3K/AKT pathway and leads to upregulation of histone H1.0, recruitment of GCN5 and AR, followed by upregulation of a subgroup of Txr genes that include ABCB1 and ABCG2. This study is the first report describing the relationship between histone H1.0 and GCN5 that cooperate to induce AR‐dependent Txr in ovarian cancer cells.     

Combination of novel HER2‐targeting antibody 1E11 with trastuzumab shows synergistic antitumor activity in HER2‐positive gastric cancer

The synergistic interaction of two antibodies targeting the same protein could be developed as an effective anti‐cancer therapy. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20–25% of breast and gastric cancer patients, and HER2‐targeted antibody therapy using trastuzumab is effective in many of these patients. Nonetheless, improving therapeutic efficacy and patient survival is important, particularly in patients with HER2‐positive gastric cancer. Here, we describe the development of 1E11, a HER2‐targeted humanized monoclonal antibody showing increased efficacy in a highly synergistic manner in combination with trastuzumab in the HER2‐overexpressing gastric cancer cell lines NCI‐N87 and OE‐19. The two antibodies bind to sub‐domain IV of the receptor, but have non‐overlapping epitopes, allowing them to simultaneously bind HER2. Treatment with 1E11 alone induced apoptosis in HER2‐positive cancer cells, and this effect was enhanced by combination treatment with trastuzumab. Combination treatment with 1E11 and trastuzumab reduced the levels of total HER2 protein and those of aberrant HER2 signaling molecules including phosphorylated HER3 and EGFR. The synergistic antitumor activity of 1E11 in combination with trastuzumab indicates that it could be a novel potent therapeutic antibody for the treatment of HER2‐overexpressing gastric cancers.     

Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes

RAS‐MAPK signaling promotes immune evasion and cancer cell survival, and MAPK inhibitors (MAPKis) are frequently used as cancer therapies. Despite progress elucidating the direct effects of MAPKi on immune cells, their indirect effect on the tumor microenvironment (TME) through changes in tumor cells remains incompletely understood. Here, we present evidence of a rapid compensatory response to MAPKi that is driven by sustained p38 MAPK signaling and by which cancer cells can upregulate the immunosuppressive protein CD73 to reduce the antitumor immune response. This compensatory response also results in decreased sensitivity toward MAPKi, and, accordingly, combining anti‐CD73 antibodies and MAPKi significantly enhances the antitumor effect compared to single‐agent treatment in vivo. Combining MAPKi and anti‐CD73 was accompanied by significant alterations in intratumor immune cell composition, supporting the effect of MAPKi‐induced CD73 expression on the TME. We show that high CD73 expression significantly correlates with worse outcome in MAPKi‐treated colorectal cancer patients, highlighting the potential clinical importance of increased CD73 expression following MAPKi treatment. Our findings may explain the diminished effect of MAPKi in cancer patients and provides further rationale for combined anti‐CD73 and MAPKi treatment.     

Inhibition of microRNA let‐7b expression by KDM2B promotes cancer progression by targeting EZH2 in ovarian cancer

MicroRNA let‐7b is a potent tumor suppressor and targets crucial oncogenes. Previous studies have shown that let‐7b expression is suppressed in ovarian cancer; however, the regulatory mechanisms of let‐7b in ovarian cancer are still not well defined. The cellular role and targets of let‐7b in ovarian cancer remain elusive. In the present study, we showed that histone demethylase, KDM2B, directly suppressed let‐7b expression by H3K36me2 demethylation. Moreover, let‐7b inhibited EZH2 expression in ovarian cancer cells. Based on these results we know that let‐7b antagonizes the enhancement of EZH2 expression caused by KDM2B overexpression, and its expression is negatively correlated with KDM2B and EZH2 expression. More importantly, proliferation, migration, and wound healing assays showed that let‐7b inhibited ovarian cancer cell proliferation and migration in vitro. Additionally, let‐7b overexpression neutralized KDM2B‐promoted cell proliferation and migration. Furthermore, downregulation of let‐7b increased the xenografted tumor volumes in nude mice that were transplanted with KDM2B‐silenced cells. EZH2 silencing reversed the tumor growth enhancement mediated by inhibition of let‐7b. Last, we show that let‐7b expression is suppressed in ovarian carcinomas and its expression is negatively associated with the clinicopathological features of ovarian cancer, including histological type, histological grade, International Federation of Gynecology and Obstetrics (FIGO) stage, and lymph node metastatic status. In conclusion, in ovarian cancer, let‐7b expression is epigenetically suppressed by high expression of KDM2B. The loss of let‐7b upregulates the expression of EZH2, which promotes ovarian cancer growth in vitro and in vivo.     

miR181b is induced by the chemopreventive polyphenol curcumin and inhibits breast cancer metastasis via down‐regulation of the inflammatory cytokines CXCL1 and ‐2

Chronic inflammation is a major risk factor for the development and metastatic progression of cancer. We have previously reported that the chemopreventive polyphenol Curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and ‐2 leading to diminished formation of breast and prostate cancer metastases. In the present study, we have analyzed the effects of Curcumin on miRNA expression and its correlation to the anti‐tumorigenic properties of this natural occurring polyphenol.Using microarray miRNA expression analyses, we show here that Curcumin modulates the expression of a series of miRNAs, including miR181b, in metastatic breast cancer cells. Interestingly, we found that miR181b down‐modulates CXCL1 and ‐2 through a direct binding to their 3′‐UTR. Overexpression or inhibition of miR181b in metastatic breast cancer cells has a significant impact on CXCL1 and ‐2 and is required for the effect of Curcumin on these two cytokines. miR181b also mediates the effects of Curcumin on inhibition of proliferation and invasion as well as induction of apoptosis. Importantly, over‐expression of miR181b in metastatic breast cancer cells inhibits metastasis formation in vivo in immunodeficient mice. Finally, we demonstrated that Curcumin up‐regulates miR181b and down‐regulates CXCL1 and ‐2 in cells isolated from several primary human breast cancers.Taken together, these data show that Curcumin provides a simple bridge to bring metastamir modulation into the clinic, placing it in a primary and tertiary preventive, as well as a therapeutic, setting.     

Anti‐FIRΔexon2 autoantibody as a novel indicator for better overall survival in gastric cancer

There is no clinically available biomarker for efficiently indicating the overall survival or therapy response of gastric cancer (GC). The autoantibodies (Abs) in the sera of anti‐far‐upstream element‐binding protein‐interacting repressor‐lacking exon2 (FIRΔexon2), anti‐sorting nexin 15, and anti‐spermatogenesis and oogenesis–specific basic helix–loop–helix 1 were markedly higher in GC patients than in healthy donors (HDs). These Abs were identified by large‐scale serological identification of antigens by recombinant cDNA expression cloning screenings and their expression levels were evaluated by amplified luminescence proximity homogeneous assay. In particular, compared with age‐matched HDs, the level of anti‐FIRΔexon2 Abs in GC patients was significantly higher (P < .001). The Spearman''s rank correlation analysis between anti‐FIRΔexon2 Abs and clinically available tumor markers such as carcinoembryonic antigen (CEA) was statistically insignificant, indicating that FIRΔexon2 Abs is an independent biomarker. We performed receiver‐operating curve analysis to evaluate the anti‐FIRΔexon2 Ab as a candidate biomarker with CEA and carbohydrate antigen 19‐9 (CA19‐9). The overall survival of GC patients with high anti‐FIRΔexon2 Abs titer was significantly favorable (P = .04) than that of GC patients who were below detection level of anti‐FIRΔexon2 Abs. However, clinical stages were not apparently correlated with the levels of anti‐FIRΔexon2 Ab, CEA, and CA19‐9. In conclusion, anti‐FIRΔexon2 Abs detected in GC patients is a potential biomarker for monitoring a better prognosis. Hence, anti‐FIRΔexon2 Abs is a promising biomarker for indicating better overall survival of gastric cancer patients.     

NLRP4 negatively regulates type I interferon response and influences the outcome in anti‐programmed cell death protein (PD)‐1/PD‐ligand 1 therapy

The challenge to improve the clinical efficacy and enlarge the population that benefits from immune checkpoint inhibitors (ICIs) for non‐small‐cell lung cancer (NSCLC) is significant. Based on whole‐exosome sequencing analysis of biopsies from NSCLC patients before anti‐programmed cell death protein‐2 (PD‐1) treatment, we identified NLRP4 mutations in the responders with a longer progression‐free survival (PFS). Knockdown of NLRP4 in mouse Lewis lung cancer cell line enhanced interferon (IFN)‐α/β production through the cGAS‐STING‐IRF3/IRF7 axis and promoted the accumulation of intratumoral CD8⁺ T cells, leading to tumor growth retardation in vivo and a synergistic effect with anti‐PD‐ligand 1 therapy. This was consistent with clinical observations that more tumor‐infiltrating CD8⁺ T cells and elevated peripheral IFN‐α before receiving nivolumab treatment were associated with a longer PFS in NSCLC patients. Our study highlights the roles of tumor‐intrinsic NLRP4 in remodeling the immune contextures in the tumor microenvironment, making regional type I IFN beneficial for ICI treatment.     

Clinical significance of BIM deletion polymorphism in chemoradiotherapy for non‐small cell lung cancer

The standard treatment for locally advanced non‐small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by anti‐programmed cell death‐ligand 1 (anti‐PD‐L1) treatment. BIM deletion polymorphism induces the suppression of apoptosis resulting from epidermal growth factor (EGFR)‐tyrosine kinase inhibitors in EGFR‐mutated NSCLC patients. We aimed to examine the effects of BIM polymorphism on CRT and anti‐PD‐L1/PD‐1 treatment in NSCLC patients. In this retrospective study of 1312 patients with unresectable NSCLC treated at Higashi‐Hiroshima Medical Center and Hiroshima University Hospital between April 1994 and October 2019, we enrolled those who underwent CRT or chemotherapy using carboplatin + paclitaxel or cisplatin + vinorelbine, or anti‐PD‐L1/PD‐1 treatment. Of 1312 patients, 88, 80, and 74 underwent CRT, chemotherapy, and anti‐PD‐L1/PD‐1 treatment, respectively, and 17.0%, 15.2% and 17.6% of these patients showed BIM polymorphism. Among patients receiving CRT, the progression‐free survival was significantly shorter in those with BIM deletion than in those without. In the multivariate analyses, BIM polymorphism was an independent factor of poor anti‐tumor effects. These results were not observed in the chemotherapy and anti‐PD‐L1/PD‐1 treatment groups. In in vitro experiments, BIM expression suppression using small interfering RNA in NSCLC cell lines showed a significantly suppressed anti‐tumor effect and apoptosis after irradiation but not chemotherapy. In conclusion, we showed that BIM polymorphism was a poor‐predictive factor for anti‐tumor effects in NSCLC patients who underwent CRT, specifically radiotherapy. In the implementation of CRT in patients with BIM polymorphism, we should consider subsequent treatment, keeping in mind that CRT may be insufficient.