The mechanism of tumor drug resistance is complex and may involve stem cell maintenance, epithelial-mesenchymal transition, the activation of survival signaling pathways, transporter protein expression, and tumor microenvironment remodeling, all of which are linked to γ-secretase/Notch signaling. Increasing evidence has shown that the activation of the γ-secretase/Notch pathway is a key driver of cancer progression and drug resistance development and that γ-secretase inhibitors (GSIs) may be the most promising agents for reversing chemotherapy resistance of tumors by targeting the γ-secretase/Notch pathway. Here, we systematically summarize the roles in supporting γ-secretase/Notch activation-associated transformation of cancer cells into cancer stem cells, promotion of the EMT process, PI3K/Akt, MEK/ERK and NF-κB activation, enhancement of ABC transporter protein expression, and TME alteration in mediating tumor drug resistance. Subsequently, we analyze the mechanism of GSIs targeting the γ-secretase/Notch pathway to reverse tumor drug resistance and propose the outstanding advantages of GSIs in treating breast cancer drug resistance over other tumors. Finally, we emphasize that the development of GSIs for reversing tumor drug resistance is promising.
To date, there are 16 types of CRF01_AE/B circulating recombinant forms identified, and most of them are distributed in Asian countries such as China, Malaysia, and Singapore. Previous HIV molecular epidemiological surveys showed that CRF01_AE (27.6%) and B (9.6%) subtypes are predominant strains in mainland of China. At the same time, the HIV-1 virus spreads faster in the men who have sex with men (MSM) population than in other risk groups. In Shanghai district, ∼66.0% of newly reported cases were infected through homosexual transmission. In this study, we report a novel recombinant strain of CRF01_AE/B. The near full-length genome phylogenetic tree showed that the strain clustered with the CRF01_AE reference sequence and placed in the peripheral position within the branch of the CRF01_AE strain. Subregional evolutionary results indicated that the CRF01_AE subtype was derived from cluster 4 of CRF01_AE, which is mainly distributed in northern China. The subtype B was correlated with the U.S./Europe B, which are widely prevalent in the Chinese MSM population. In recent years, a large number of recombinant forms between CRF01_AE and B strains are continuously emerging in China. Therefore, understanding the current epidemic recombinant forms will have significant implications for prevention and treatment of HIV/AIDS.