Targeting SHP2 reverses BRAF inhibitor tolerance in anaplastic thyroid carcinoma.

PURPOSE: To explore the possibility of a combination of dabrafenib and SHP2 inhibitor in the treatment of anaplastic thyroid carcinoma and to provide a new therapeutic strategy for the treatment of anaplastic thyroid cancer. PATIENTS AND METHODS: Firstly, a drug resistance model was established, and the expression levels of related RTK were detected by qPCR. Western blot was used to detect the protein expression levels of Akt and MAPK signaling pathways in the control group, single-drug group and two-drug combination group. The gene silencing of SHP2 was achieved by transfection of siRNA and verified by Western blot. CCK8 kit and clone formation assay were used to detect cell proliferation activity. In vivo model of mutant thyroid cancer cells was established by subcutaneous injection of mice and then divided into four groups. Tumor diameter was measured every two days. Immunohistochemistry was used to evaluate the expression of p-ERK, p-AKT and Ki67 in mouse tumors. RESULTS: In this study, dabrafenib-resistant ATC cells were first constructed, and the response of RTKs in drug-resistant cells was upregulated to activate Akt and MER/ERK pathways. The activation of Akt and MEK/ERK pathways in the combination group was significantly inhibited, and the proliferation ability of tumor cells was significantly reduced compared with Dabrafenib, SHP099 group and DMSO group. To verify that SHP099 was not off-target, we also silenced SHP2 expression by transfection with siRNA and obtained the same results. Finally, by building a mouse drug resistance model, we confirmed that dabrafenib and SHP099 can also play a powerful anti-cancer effect in vivo. CONCLUSION: The SHP2 inhibitor SHP099 can effectively reverse the drug resistance of dabrafenib through inhibiting the reactivated RAS signaling pathway in anaplastic thyroid cancer.The combination of dabrafenib with SHP2 inhibitor has shown significant tumor suppressive effects for dabrafenib-resistant cells and it may be a new therapeutic strategy with longer lasting therapeutic benefits.

Long-term anti-inflammatory diet in relation to improved breast cancer prognosis: a prospective cohort study.

Inflammation-modulating nutrients and inflammatory markers are established cancer risk factors, however, evidence regarding the association between post-diagnosis diet-associated inflammation and breast cancer survival is relatively sparse. We aimed to examine the association between post-diagnosis dietary inflammatory index (DII®) and risks of all-cause and breast cancer-specific mortality. A total of 1064 female breast cancer survivors in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) Trial prospective cohort, were included in this analysis if they had completed the diet history questionnaire (DHQ). Energy-adjusted DII (E-DIITM) scores were calculated based on food and supplement intake. Cox regression and competing risk models were used to estimate multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (95% CIs) by E-DII tertile (T) for all-cause and breast cancer-specific mortality. With median follow-up of 14.6 years, there were 296 (27.8%) deaths from all causes and 100 (9.4%) breast cancer-specific death. The E-DII was associated with all-cause mortality (HR T3 vs T1, 1.34; 95% CI, 1.01-1.81; P trend, 0.049, Table 2) and breast cancer mortality (HR T3 vs T1, 1.47; 95% CI, 0.89-2.43; P trend, 0.13; multivariable-adjusted HR for 1-unit increment: 1.10; 95% CI: 1.00-1.22). Non-linear positive dose-response associations with mortality from all causes were identified for E-DII scores (P non-linearity < 0.05). The post-diagnosis E-DII was statistically significantly associated with mortality risk among breast cancer survivors. Long-term anti-inflammatory diet might be a means of improving survival of breast cancer survivors.

Development and validation of nomograms integrating immune-related genomic signatures with clinicopathologic features to improve prognosis and predictive value of triple-negative breast cancer: A gene expression-based retrospective study.

PURPOSE: Accumulating evidence indicated that triple-negative breast cancer (TNBC) can stimulate stronger immune responses than other subtypes of breast cancer. We hypothesized that integrating immune-related genomic signatures with clinicopathologic factors may yield a predictive accuracy exceeding that of the currently available system. METHODS: Ten signatures that reflect specific immunogenic or immune microenvironmental features of TNBC were identified and re-analyzed using bioinformatic methods. Then, clinically annotated TNBC (n = 711) with the corresponding expression profiles, which predicted a patient's probability of disease-free survival (DFS) and overall survival (OS), was pooled to evaluate their prognostic values and establish a clinicopathologic-genomic nomogram. Three and two immune features were, respectively, selected out of 10 immune features to construct nomogram for DFS and OS prediction based on multivariate backward stepwise Cox regression analyses. RESULTS: By integrating the above immune expression signatures with prognostic clinicopathologic features, clinicopathologic-genomic nomograms were cautiously constructed, which showed reasonable prediction accuracies (DFS: HR, 1.79; 95% CI, 1.46-2.18, P < 0.001; AUC, 0.71; OS: HR, 1.96; 95% CI, 1.54-2.49; P < 0.001; AUC, 0.73). The nomogram showed low-risk subgroup had higher immune checkpoint molecules (PD-L1, PD-1, CTLA-4, LAG-3) expression and benefited from radiotherapy (HR, 0.2, 95% CI, 0.05-0.89; P = 0.034) rather than chemotherapy (HR, 1.26, 95% CI, 0.66-2.43; P = 0.485). CONCLUSIONS: These findings offer evidence that immune-related genomic data provide independent and complementary prognostic information for TNBC, and the nomogram might be a practical predictive tool to identify TNBC patients who would benefit from chemotherapy, radiotherapy, and upcoming popularity of immunotherapy.

Survival Comparisons Between Early Male and Female Breast Cancer Patients.

We aimed to compare the overall survival (OS) and standardized mortality rate (SMR) of the male breast cancer (MBC) with female breast cancer (FBC) after propensity score matching. Based on the Surveillance, Epidemiology, and End Results (SEER), the early breast cancer patients (T1-2N0-2M0) were extracted from 1998-2007. This study included 1,111 and 2,151 patients with early MBC and FBC, respectively, whose clinicopathological characteristics were well balanced. At a mean follow-up time of 97 months, 10-year OS rate was 58.3% in the MBC group and 68.7% in the FBC (log-rank test, P < 0.001; hazard ratio (HR) = 1.45, 95% confidence interval (CI) = 1.29 to 1.64). Adjusted HR for OS between MBC and FBC were revealed from propensity score matched-multivariable Cox proportional hazards models (HR = 1.53, 95% CI = 1.35 to 1.73). Similar adjusted SMRs between MBC and FBC ((SMR = 1.98, 95% CI = 1.83,2.14) for FBC and (SMR = 2.07, 95% CI = 1.88-2.28) for MBC) were observed. The nomogram was constructed for FBC, and predicted probabilities were generally good (C-index = 0.71), whose area under curve is higher than TNM stage classification (0.74 vs 0.62). OS was significantly decreased among early MBC patients compared with FBC, but similar SMRs and its trends by age groups were observed between MBC and FBC except for young patients.

A Potential Prognostic Long Noncoding RNA Signature to Predict Recurrence among ER-positive Breast Cancer Patients Treated with Tamoxifen.

Limited predictable long noncoding RNA (lncRNA) signature was reported in tamoxifen resistance among estrogen receptor (ER)-positive breast cancer (BC) patients. The aim of this study was to identify and assess prognostic lncRNA signature to predict recurrence among ER-positive BC patients treated with tamoxifen. Cohorts from Gene Expression Omnibus (GEO) (n = 298) and The Cancer Genome Atlas (TCGA) (n = 160) were defined as training and validation cohort, respectively. BC relapse associated lnRNAs was identify within training cohort, and the predictable value of recurrence was assessed in both cohorts. A total of 11lncRNAs were recognized to be associated with relapse free survival (RFS) of ER-positive BC patients receiving tamoxifen, who were divided into low-risk and high-risk group on basis of relapse risk scores (RRS). Multivariate cox regression analyses revealed that the RRS is an independent prognostic biomarker in the prediction of ER-positive BC patients' survival. GSEA indicated that high-risk group was associated with several signaling pathways in processing of BC recurrence and metastasis such as PI3K-Akt and Wnt signaling. Our 11-lncRNA based classifier is a reliable prognostic and predictive tool for disease relapse in BC patients receiving tamoxifen.

Sestrin 2 suppresses cells proliferation through AMPK/mTORC1 pathway activation in colorectal cancer.

Sestrin 2 is a conserved antioxidant protein that reduces reactive oxygen species (ROS) and inhibits mammalian target of rapamycin complex 1 (mTORC1). We previously showed that sestrin 2 is abnormally decreased in colorectal cancer (CRC). To elucidate the molecular mechanism behind the potential contribution of sestrin 2 to CRC, we used a lentiviral expression vector system to determine the effects of sestrin 2 overexpression on human CRC cells. We found that sestrin 2 overexpression decreased ROS production, inhibited cell growth, and stimulated apoptosis in two CRC cell lines. In parallel, expression of the proliferation marker PCNA was decreased, proapoptotic caspase 3, 7, and 9 levels were increased, and expression of the anti-apoptotic protein survivin was reduced. Sestrin 2 overexpression also activated the adenosine monophosphate-activated protein kinase (AMPK) pathway, and suppressed mTORC1 signaling. Treating CRC cells with compound C, an AMPK inhibitor, reversed or attenuated changes in proliferation, apoptosis, and signaling proteins of the AMPK/mTORC1 axis. In a xenograft mouse model, CRC growth was attenuated by sestrin 2 overexpression. These results suggest that sestrin 2 suppresses CRC cell growth through activation of the AMPK/mTORC1 pathway and induction of apoptosis, and could be a novel pharmacological target for the treatment of CRC.