No abstract

Long non-coding RNAs (lncRNAs) are a novel class of regulatory genes that play critical roles in various processes ranging from normal development to human diseases such as cancer progression. Recent studies have shown that lncRNAs regulate the gene expression by chromatin remodelling, transcription, splicing and RNA decay control, enhancer function, and epigenetic regulation. However, little is known about translation regulation by lncRNAs. We identified a translational regulatory lncRNA (treRNA) through genomewide computational analysis. We found that treRNA is upregulated in paired clinical breast cancer primary and lymph-node metastasis samples, and that its expression stimulates tumour invasion in vitro and metastasis in vivo. Interestingly, we found that treRNA downregulates the expression of the epithelial marker E-cadherin by suppressing the translation of its mRNA. We identified a novel ribonucleoprotein (RNP) complex, consisting of RNA-binding proteins (hnRNP K, FXR1, and FXR2), PUF60 and SF3B3, that is required for this treRNA functions. Translational suppression by treRNA is dependent on the 3 0 UTR of the E-cadherin mRNA. Taken together, our study indicates a novel mechanism of gene regulation by lncRNAs in cancer progression.

Metastasis is a critical event affecting breast cancer patient survival. To identify molecules contributing to the metastatic process, we analysed The Cancer Genome Atlas (TCGA) breast cancer data and identified 41 genes whose expression is inversely correlated with survival. Here we show that GABAA receptor alpha3 (Gabra3), normally exclusively expressed in adult brain, is also expressed in breast cancer, with high expression of Gabra3 being inversely correlated with breast cancer survival. We demonstrate that Gabra3 activates the AKT pathway to promote breast cancer cell migration, invasion and metastasis. Importantly, we find an A-to-I RNA-edited form of Gabra3 only in non-invasive breast cancers and show that edited Gabra3 suppresses breast cancer cell invasion and metastasis. A-to-I-edited Gabra3 has reduced cell surface expression and suppresses the activation of AKT required for cell migration and invasion. Our study demonstrates a significant role for mRNA-edited Gabra3 in breast cancer metastasis.

9501 Background: NIVO + IPI was shown to improve overall survival (OS) and durability of response vs chemo in 1L advanced NSCLC in CheckMate 227 Part 1, regardless of PD-L1 expression. We hypothesized that a limited course of chemo combined with NIVO + IPI could provide rapid disease control while building on the durable OS benefit seen with dual PD-1 and CTLA-4 inhibition. CheckMate 9LA (NCT03215706) is a phase 3 randomized study evaluating NIVO + IPI + 2 cycles chemo vs chemo in 1L stage IV/recurrent NSCLC. Methods: Adults with tx-naive, histologically confirmed stage IV/recurrent NSCLC, ECOG performance status 0–1, and no known sensitizing EGFR/ALK alterations were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles) (n = 361) or chemo (4 cycles) alone (n = 358), stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous). Chemo was based on histology. Pts with non-squamous NSCLC in the chemo-only arm could receive optional pemetrexed maintenance. Pts were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 y. The primary endpoint was OS; the interim analysis using Lan–DeMets alpha spending function with O’Brien–Fleming boundary was planned at ~80% information fraction (ie, after observing ~322 total events). Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability. Results: Baseline characteristics were balanced across arms. At a preplanned interim analysis (minimum follow-up 8.1 mo), OS was significantly prolonged with NIVO + IPI + chemo vs chemo (HR 0.69, 96.71% CI: 0.55–0.87; P = 0.0006); statistically significant improvements in PFS and ORR were seen. With longer follow-up (minimum 12.7 mo), NIVO + IPI + chemo vs chemo continued to provide longer OS; median 15.6 vs 10.9 mo (HR 0.66, 95% CI: 0.55–0.80); 1-y OS rates were 63 vs 47%. Clinical benefit was consistent across all efficacy measures in key subgroups including by PD-L1 and histology. Grade 3–4 tx-related adverse events were reported in 47 vs 38% of pts in the NIVO + IPI + chemo vs chemo arms, respectively. Conclusions: CheckMate 9LA met its primary endpoint: a statistically significant improvement in OS was observed with NIVO + NSCLC-optimized IPI + a limited course of chemo vs chemo (4 cycles) in 1L advanced NSCLC. No new safety signals were reported. Clinical trial information: NCT03215706 .

Gallbladder cancer represents the most common malignancy of the biliary tract and is highly lethal with less than 5% overall 5-year survival rate. Chemotherapy remains the major treatment for late-stage patients. However, insensitivity to these chemotherapeutic agents including cisplatin is common. MicroRNAs (miRNAs) have been shown as modulators of drug resistance in many cancer types. We used genome-wide gene expression analysis in clinical samples to identify miR-125b-5p down-regulated in gallbladder cancer. miR-125b-5p up-regulation promoted cell death in gallbladder cancer cells in the presence of cisplatin. In contrast, knockdown of miR-125b-5p reduced cell death in gallbladder cancer cells treated with cisplatin. Up-regulation of miR-125b-5p significantly decreased tumor growth in combination with cisplatin in a mouse model. We identified Bcl2 as a direct target of miR-125b-5p which mediates the function of miR-125b-5p in gallbladder cancer. In clinical samples, miR-125b-5p was down-regulated in gallbladder cancer whereas Bcl2 was up-regulated and their expression was inversely correlated. Moreover, low miR-125b-5p expression or high expression of Bcl2 is correlated with poor prognosis in gallbladder cancer. Taken together, our findings indicate that miR-125b-5p is a potent chemotherapy sensitizer and may function as a new biomarker for the prognosis of gallbladder cancer patients.