Cxcl10 chemokine induces migration of ING4-deficient breast cancer cells via a novel crosstalk mechanism between the Cxcr3 and Egfr receptors

The chemokine Cxcl10 has been associated with poor prognosis in breast cancer, but the mechanism is not well understood. Our previous study have shown that CXCL10 was repressed by the ING4 tumor suppressor, suggesting a potential inverse functional relationship. We thus investigated a role for Cxcl10 in the context of ING4 deficiencies in breast cancer. We first analyzed public gene expression datasets and found that patients with CXCL10 -high/ ING4 -low expressing tumors had significantly reduced disease-free survival in breast cancer. In vitro , Cxcl10 induced migration of ING4 -deleted breast cancer cells, but not of ING4 -intact cells. Using inhibitors, we found that Cxcl10-induced migration of ING4 -deleted cells required Cxcr3, Egfr, and the Gβγ subunits downstream of Cxcr3, but not Gαi. Immunofluorescent imaging showed that Cxcl10 induced early transient colocalization between Cxcr3 and Egfr in both ING4 -intact and ING4 -deleted cells, which recurred only in ING4 -deleted cells. A peptide agent that binds to the internal juxtamembrane domain of Egfr inhibited Cxcr3/Egfr colocalization and cell migration. Taken together, these results presented a novel mechanism of Cxcl10 that elicits migration of ING4 -deleted cells, in part by inducing a physical or proximal association between Cxcr3 and Egfr and signaling downstream via Gβγ. These results further indicated that ING4 plays a critical role in the regulation of Cxcl10 signaling that enables breast cancer progression.

Carvacrol: An In Silico Approach of a Candidate Drug on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR Receptors in the Breast Cancer

Carvacrol is a phenol monoterpene found in aromatic plants specially in Lamiaceae family, which has been evaluated in an experimental model of breast cancer. However, any proposed mechanism based on its antitumor effect has not been reported. In our previous study, carvacrol showed a protective effect on 7,12-dimethylbenz[α]anthracene- (DMBA-) induced breast cancer in female rats. The main objective in this research was to evaluate by using in silico study the carvacrol on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR receptors involved in breast cancer progression by docking analysis, molecular dynamic, and drug-likeness evaluation. A multilevel computational study to evaluate the antitumor potential of carvacrol focusing on the main targets involved in the breast cancer was carried out. The in silico study starts with protein-ligand docking of carvacrol followed by ligand pathway calculations, molecular dynamic simulations, and molecular mechanics energies combined with the Poisson–Boltzmann (MM/PBSA) calculation of the free energy of binding for carvacrol. As result, the in silico study led to the identification of carvacrol with strong binding affinity on mTOR receptor. Additionally, in silico drug-likeness index for carvacrol showed a good predicted therapeutic profile of druggability. Our findings suggest that mTOR signaling pathway could be responsible for its preventive effect in the breast cancer.

Results of monoclonal antibodies against EGFR-receptors application in patients with metastatic colorectal cancer (mCRC).

e14701 Background: Monoclonal antibodies against the epidermal growth factor receptor(EGFR)are standard components of treatment in mCRC.This study was designed to evaluate the tolerability and efficacy of the combinations of Panitumumab(P) and Cetuximab(C) with chemotherapy in patients with wild type(WT) KRAS tumors mCRC. Methods: Mutation analysis of KRAS(codons12,13) was done on samples at diagnosis. Key elegibility criteria included measurable mCRC stage IV, ECOG ≤2, adequate liver,kidney and bone marrow function, no brain metastases. P was administered 6mg/ kg 1 day q2w. C was administered 400mg/m² 1day and 250mg/m² q1w. Combination with FOLFOX-6 or FOLFIRI pegimens was allowed. Endpoints include response rate, OS, PFS and safety. Results: Of 38 testable samples there were 21(55.3%) WT KRAS tumors. All of these 21 (13male and 8female) pts were recruited. Mean age was 58.1±12.3. Synchronous metastases had 33.3%(7pts). Majority of pts benefited from anti-EGFR combined with cytotoxic chemotherapy 80.9% (17), mostly FOLFIRI – 57,1%(12).There were23.8%(5) in the 1st line CT, 76.1%(16) in the 2nd line CT. 6 mos of the treatment were analyzed. Overall RR was76.1 %(16) including 6PR(28.5%) and 10SD(47.6%). Med OS= 9.1mo, Med PFS= 4.3mo. 8 pts(38.1%) are alive till the abstract submission. Most common toxicities were:skin rash 2/3Gd.-90.5%(19), xeroderma 2Gd.-42.9%(9),skin itch 1/3Gd.-42.9%(9), paronychia 2Gd. -14.2%(3), purulent psorophthalmia 2Gd.-14.2%(3). All kinds of toxicities were controlled by symptomatic medication if necessary and did not lead to anti-EGFR agents dalay. Besides,diarrhea 1/2Gd.- 66.7%(14), 3Gd.-14.3%(3), neutropenia 1/2Gd.-28.6%(6), 3/4Gd.-9.5%(2), nausea 3/4Gd.- 14.3%(3), vomiting 1/2Gd.- 42.9%(9), fatigue 1/2Gd.-47.6%(10). Conclusions: These results consider significant efficacy of anti-EGFR agents combined with CT in pts with mCRC. Controlled toxicity of the therapy allows to use it widely.