Lapatinib Decreases the Preimplantation Aneuploidy Rate of in vitro Fertilized Mouse Embryos without Affecting Completion of Preimplantation Development
CYTOGENETIC AND GENOME RESEARCH
Authors: Maleki, Parvaneh; Gourabi, Hamid; Tahmaseb, Mohammad; Golkar-Narenji, Afsaneh; Bazrgar, Masood
Abstract
One of the major reasons for implantation failure and spontaneous abortion is a high incidence of preimplantation chromosomal aneuploidy. Lapatinib simultaneously inhibits EGFR and HER2, leading to apoptosis. We hypothesized a higher sensitivity for aneuploid cells in preimplantation embryos to lapatinib based on reports of aneuploid cell lines being sensitive to some anticancer drugs. Late 2-cell mouse embryos were treated with lapatinib after determining a nontoxic dose. Morphologies were recorded 24, 48, and 60 hours later. The effect of lapatinib on the aneuploidy rate was evaluated by studying blastocyst cells using FISH. Although the rate of development to 8-cell and morula stage was higher in the control group (p < 0.05), there was no difference in development to the blastocyst stage at the same studied intervals between lapatinib-treated and control groups (p = 0.924). The mean number of cells in morula and blastocyst stages were not different between the groups (p = 0.331 and p = 0.175, respectively). The frequency of aneuploid cells and diploid embryos was, respectively, significantly lower and higher in lapatinib-treated embryos, (p < 0.001). Since lapatinib treatment reduced the aneuploidy rate without impact on the development of mouse preimplantation embryos to the blastocyst stage and number of total cells, lapatinib seems useful for prevention of preimplantation aneuploidy in in vitro fertilization.
Proteolysis targeting chimera (PROTAC) for epidermal growth factor receptor enhances anti-tumor immunity in non-small cell lung cancer
DRUG DEVELOPMENT RESEARCH
Authors: Wang, Kai; Zhou, Hongping
Abstract
While immunotherapy has dramatically revolutionized the treatment of non-small cell lung cancer (NSCLC), it still faces challenges such as low therapeutic efficacy and immune-related adverse events, indicating that safe and effective approaches to enhance NSCLC immunotherapy are still highly demanded. Epidermal growth factor receptor (EGFR) is an established target for molecularly targeted therapy of NSCLC. Overexpression and activating mutations of EGFR can promote the resistance of NSCLC to immunotherapy via upregulating inhibitory immune checkpoints such as programmed death receptor ligand 1 (PD-L1) and indoleamine-2,3-dioxygenase-1 (IDO1). Thus, therapeutic inhibition of EGFR also holds promise in modulating the immune microenvironment to advance NSCLC immunotherapy. In this study, we employed a proteolysis targeting chimera (PROTAC) that degrades EGFR(L858R) to investigate its potential in dually inhibiting PD-L1 and IDO1 to potentiate the anti-tumor immunity in NSCLC. We demonstrated that PROTAC significantly downregulated the protein levels of both PD-L1 and IDO1 in NSCLC H3255 cell and tumor. We also confirmed that PROTAC significantly suppressed the H3255 tumor growth and enhanced the anti-tumor immune response in H3255 tumor. Overall, our study provides a novel strategy for future NSCLC therapy.
COA
Publication 
1.jpg)
Loading ......
