PubMed · 13526253
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J KRETZ. 1958. For dosing Bayer E 39.. https://pubmed.ncbi.nlm.nih.gov/13526253/
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Drug response differs substantially in cancer patients due to inter- and intra-tumor heterogeneity. Particularly, transcriptome context, especially tumor microenvironment, has been shown playing a significant role in shaping the actual treatment outcome. In this study, we develop a deep variational autoencoder (VAE) model to compress thousands of genes into latent vectors in a low-dimensional space. We then demonstrate that these encoded vectors could accurately impute drug response, outperform standard signature-gene based approaches, and appropriately control the overfitting problem. We apply rigorous quality assessment and validation, including assessing the impact of cell line lineage, cross-validation, cross-panel evaluation, and application in independent clinical data sets, to warrant the accuracy of the imputed drug response in both cell lines and cancer samples. Specifically, the expression-regulated component (EReX) of the observed drug response achieves high correlation across panels. Using the well-trained models, we impute drug response of The Cancer Genome Atlas data and investigate the features and signatures associated with the imputed drug response, including cell line origins, somatic mutations and tumor mutation burdens, tumor microenvironment, and confounding factors. In summary, our deep learning method and the results are useful for the study of signatures and markers of drug response.
CYPs (cytochrome P450s) catalyze the conversion of numerous numbers of xenobiotics including carcinogens and drugs. CYPs can be involved in metabolic pathways of activation of procarcinogens and/or inactivation of carcinogens during the tumorigenic processes. Recently, increasing number of cancer tissues as well as normal tissues have been found to express a variety of CYPs. The local expression of CYPs in tumors appears to be very important for the management of cancers since CYPs expressed in tumors may be involved in activation and/or inactivation of anticancer drugs. The expression of CYPs in tumors may also convert endogenous substrates to metabolites that facilitate cancer development. In this review, we summarize the association of CYP expression in cancer tissues with carcinogenesis and cancer treatment.
Apo2L/TRAIL (tumor necrosis factor-related apoptosis inducing ligand (TRAIL), also known as Apo2L) is a potentially important anticancer agent awaiting clinical trials. Unfortunately, however, some cancer cells exhibit resistance to Apo2L/TRAIL, which could limit the use of this potentially promising anticancer agent. Although the molecular basis of the inherent or acquired resistance to Apo2L/TRAIL remains unclear, previous studies indicate that Bax deficiency can confer resistance to Apo2L/TRAIL. Proteasome inhibition is also emerging as a promising therapeutic strategy to manage human malignancies. Here, we report that proteasome inhibitor MG132 upregulates Apo2L/TRAIL death receptor 5 expression in both Bax-proficient and -deficient HCT116 cells. MG132 effectively cooperated with Apo2L/TRAIL to induce apoptosis in both Bax-proficient and -deficient cells that was coupled with caspases-8 and -3 activation and Bid cleavage. Although both agents in combination also induced cytochrome c and Smac release from mitochondria into cytosol and activated caspase-9 in Bax-proficient cells, their effects on these events were significantly diminished in Bax-deficient cells. These results suggest that Bax is not absolutely required for death receptor 5-dependent apoptotic signals and MG132 by upregulating DR5 effectively cooperates with Apo2L/TRAIL to overcome Bax deficiency-induced resistance to Apo2L/TRAIL. Our results have important clinical implications in that the use of Apo2L/TRAIL and proteasome inhibitors in combination could prove to be a novel therapeutic strategy to manage the Apo2L/TRAIL-resistant tumors.