The specific mutations in the EGFR gene of

The specific mutations in the EGFR gene of NSCLC are correlated with clinical responsiveness to the TKI gefitinib. These mutations lead to the increase of growth factor signaling and susceptibility to the inhibitor. Such mutations in NSCLC lead to the good response to cetuximab and panitumumab that could bind to the extracellular domain of EGFR. Among the downstream pathways, the RAS-RAF-MAPK, PI3K-PTEN-AKT, and JAK/STAT pathways have also been implicated in the resistance mechanisms against antibody-mediated EGFR inhibition. Any alterations or mutations in their components, such as KRAS, NRAS, BRAF, and PIK3CA gene, can influence the activation of EGFR and lead to drug resistance. Recently, the third-generation EGFR inhibitors, such as osimertinib, rociletinib and olmutinib were developed in targeting T790M. These mutant-selective EGFR-TKIs expressed a good effect in overcoming T790M-mediated resistance in patients with NSCLC.
Drug detoxification and inactivation Tumor resistance may be present at the beginning of treatment, develop during treatment, or become apparent on re-treatment of the patient. The mechanisms involved are usually inferred from experiments of Di Nicolantonio F et al. Clonal selection in this process was that cell lines produced highly resistant sub-clones on the low concentrations of drugs exposure. However, Romidepsin may be able to adapt by regulation of expression of resistance or target molecules individually if they survived the initial exposure to the drug and did not require clonal selection. This required changes in molecular levels such as epigenetic change and mutation mechanisms. Glutathione S-transferase (GST) was important for the development of drug resistance via direct detoxification. It may decrease the concentration of anticancer drugs via the glutathione (GSH)-conjugate export pump and special emphasis has been put on the function of GSTs in Phase II detoxification. Drozd E et al. indicated that expression of GSTM1 and GSTA1-3 genes was up-regulated by doxorubicin treatment and suggested that activity of these genes may be associated with drug resistance. It has been shown that cancer cells could develop cisplatin resistance through enhancing the drug detoxification system by elevating the levels of intracellular scavengers such as GSH in treatment in ovarian, testicular, cervical cancer and other cancer types. The detoxification of cisplatin by its interaction with GSH may be catalyzed by GST. Other GSH-related enzymes may be also important in this resistance process. In the research of Khalil et al., they showed that Nuclear erythroid related factor-2 (NRF2) was known to promote cancer therapeutic detoxification and crosstalk with growth-promoting pathways. Here they reported HER2 targeting by antibodies (eg. Trastuzumab and Pertuzumab) inhibited growth in association with persistent generation of reactive oxygen species (ROS), GSH depletion, reduction in NRF2 levels and inhibition of NRF2 function in ovarian cancer cell lines. Several therapeutic strategies such as anticancer chemotherapy largely depended on ROS generation to induce cytotoxicity. Hyper-activation of NRF2 dependent AR pathway would attenuate the potency of such agents.
Impact on apoptosis The suppression of apoptosis is one mechanism by which tumor cells become drug resistant. Why cytotoxic drugs fail to kill sufficient tumor cells in the major human solid cancers, such as the carcinomas, was suggested to be due to the inherent inability of these cells to engage apoptosis after drug-induced damage. Drug resistance mediated by anti-apoptosis is also a key MDR mechanism. B-cell leukemia/lymphoma-2 (BCL-2) was considered to be one of the primary anti-apoptotic proteins. The BCL-2 family of proteins regulated cell fate by controlling the mitochondrial apoptotic pathway. When activated, the pro-apoptotic members Bak and Bax could form high molecular weight oligomers on the mitochondrial membrane, which promoted dissipation of mitochondrial membrane potential and allowed the release of cytochrome to the cytoplasm and consequently activating the caspases. In turn, the pro-survival members, such as Bclxl, Bcl2, and Mcl-1, binded Bak and Bax and prevented their activation and oligomerization. Thus, this family of proteins served as rheostats for mitochondrial membrane stability and is critical in the cell’s life or death decisions.