Abstract
Drug resistance is a major cause of deaths from cancer. E2F1 is a transcription factor involved in cell proliferation, apoptosis. and metastasis through an intricate regulatory network, which includes other transcription factors like p73 and cancer-related microRNAs like miR-205. To investigate the emergence of drug resistance, we developed a methodology that integrates experimental data with a network biology and kinetic modeling. Using a regulatory map developed to summarize knowledge on E2F1 and its interplay with p73/DNp73 and miR-205 in cancer drug responses, we derived a kinetic model that represents the network response to certain genotoxic and cytostatic anticancer drugs. By perturbing the model parameters, we simulated heterogeneous cell configurations referred to as in silico cell lines. These were used to detect genetic signatures characteristic for single or double drug resistance. We identified a signature composed of high E2F1 and low miR-205 expression that promotes resistance to genotoxic drugs. In this signature, downregulation of miR-205, can be mediated by an imbalance in the p73/DNp73 ratio or by dysregulation of other cancer-related regulators of miR-205 expression such as TGFβ-1 or TWIST1. In addition, we found that a genetic signature composed of high E2F1, low miR-205, and high ERBB3 can render tumor cells insensitive to both cytostatic and genotoxic drugs. Our model simulations also suggested that conventional genotoxic drug treatment favors selection of chemoresistant cells in genetically heterogeneous tumors, in a manner requiring dysregulation of incoherent feedforward loops that involve E2F1, p73/DNp73, and miR-205.
Highlights
Resistance to genotoxic drugs as the major cause of cancer therapy failure is a serious problem for oncologists and their patients that requires the understanding of the pivotal triggering events and its evolution when cancer progresses
We investigated whether this system is part of a wider and more complex network regulating the response of tumor cells to anticancer drugs
For p73 and DNp73 synthesis; ii) given that overexpression of E2F1 is associated with aggressiveness and chemoresistance [4,15], we considered iterative modulation of E2F1 and DNp73 synthesis parameters to test whether their dysregulation suffices to induce resistance; (iii) considering that dysregulation of TGFb-1 signaling promotes invasion and metastasis [30], we modified the E2F1 synthesis parameter and TGFb-1 expression level to investigate whether they can synergize in the emergence of a resistance phenotype; and (iv) given that the expression of ERBB3 associates to the resistance to certain cytostatic drugs [20,31,32], we modified E2F1 and ERBB3 synthesis parameters to test whether their combined dysregulation can cause enhanced chemoresistance
Summary
Resistance to genotoxic drugs as the major cause of cancer therapy failure is a serious problem for oncologists and their patients that requires the understanding of the pivotal triggering events and its evolution when cancer progresses. Chemoresistance can be innate or acquired and may attributable to a single agent or a class of drugs. Potential mechanisms to counteract the therapeutic effects of DNA-damaging agents include the reduction of effective drug concentrations via enhanced efflux, detoxification enzymes or drug sequestration, modification of drug targets, changes or mutation in mitotic checkpoint signals, and hyperactivation of DNA repair mechanisms [1]. The cellular transcription factor E2F1 is a unique member of the E2F family of proteins as it regulates the tumor suppressor. O. Wolkenhauer and B.M. Pu€tzer contributed to this work
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