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Small molecule inhibitors, such as lapatinib, are effective against breast cancer in clinical trials , but tumor cells ultimately acquire resistance to the drug. Maintaining sensitization to drug action is essential for durable growth inhibition. Recently, adaptive reprogramming of signaling circuitry has been identified as a major cause of acquired resistance. We developed a computational framework using a Bayesian statistical approach to model signal rewiring in acquired resistance. We used the p 1-model to infer potential aberrant gene-pairs with differential posterior probabilities of appearing in resistant-vs-parental networks. Results were obtained using matched gene expression profiles under resistant and parental conditions. Using two lapatinib-treated ErbB2-positive breast cancer cell-lines: SKBR3 and BT474, our method identified similar dysregulated signaling pathways including EGFR-related pathways as well as other receptor-related pathways, many of which were reported previously as compensatory pathways of EGFR-inhibition via signaling cross-talk. A manual literature survey provided strong evidence that aberrant signaling activities in dysregulated pathways are closely related to acquired resistance in EGFR tyrosine kinase inhibitors. Our approach predicted literature-supported dysregulated pathways complementary to both node-centric (SPIA, DAVID, and GATHER) and edge-centric (ESEA and PAGI) methods. Moreover, by proposing a novel pattern of aberrant signaling called V-structures, we observed that genes were dysregulated in resistant-vs-sensitive conditions when they were involved in the switch of dependencies from targeted to bypass signaling events. A literature survey of some important V-structures suggested they play a role in breast cancer metasta-sis and/or acquired resistance to EGFR-TKIs, where the mRNA changes of TGFBR2, LEF1 and TP53 in resistant-vs-sensitive conditions were related to the dependency switch from targeted to bypass signaling links. Our results suggest many signaling pathway structures are compromised in acquired resistance, and V-structures of aberrant signaling within/ among those pathways may provide further insights into the bypass mechanism of targeted inhibition.

Data-driven models of signalling networks are becoming increasingly important in systems biology in order to reflect the dynamic patterns of signalling activities in a context-specific manner. State-of-the-art approaches for categorising and detecting signalling cross-talks may not be suitable for such models since they rely on static topologies of cell signalling networks and prior biological knowledge. In this chapter, we review state-of-the-art approaches that categorise all possible cross-talks in signalling networks and propose a novel categorisation specific to data-driven network models. Considering such models as undirected networks, we propose two categories of signalling cross-talks between any two given signalling pathways. In a Type-I cross-talk, a signalling link {g i ,g j } connects two signalling pathways, where g i and g j are signalling nodes that belong to two distinct pathways. In a Type-II cross-talk, two signalling links {g i ,g j } and {g j ,g k } meet at the intersection of two signalling pathways at a shared signalling node g j. We compared our categorisation approach with others and found that all the types of cross-talks defined by those approaches can be mapped to Type-I and Type-II cross-talks when underlying signalling activities are considered as non-causal relationships. Next, we provided a simple but intuitive algorithm called XDaMoSiN (cross-talks in data-driven models of signalling networks) to detect both Type-I and Type-II cross-talks between any two given signalling pathways in a data-driven network model. By detecting cross-talks in such network models, our approach can be used to analyse and decipher latent mechanisms of various cell phenotypes, such as cancer or acquired drug resistance, that may evolve due to the highly adaptable and dynamic nature of signal transduction networks.

Background: Initial success of inhibitors targeting oncogenes is often followed by tumor relapse due to acquired resistance. In addition to mutations in targeted oncogenes, signaling cross-talks among pathways play a vital role in such drug inefficacy. These include activation of compensatory pathways and altered activities of key effectors in other cell survival and growth-associated pathways. Results: We propose a computational framework using Bayesian modeling to systematically characterize potential cross-talks among breast cancer signaling pathways. We employed a fully Bayesian approach known as the p 1-model to infer posterior probabilities of gene-pairs in networks derived from the gene expression datasets of ErbB2-positive breast cancer cell-lines (parental, lapatinib-sensitive cell-line SKBR3 and the lapatinib-resistant cell-line SKBR3-R, derived from SKBR3). Using this computational framework, we searched for cross-talks between EGFR/ErbB and other signaling pathways from Reactome, KEGG and WikiPathway databases that contribute to lapatinib resistance. We identified 104, 188 and 299 gene-pairs as putative drug-resistant cross-talks, respectively, each comprised of a gene in the EGFR/ErbB signaling pathway and a gene from another signaling pathway, that appear to be interacting in resistant cells but not in parental cells. In 168 of these (distinct) gene-pairs, both of the interacting partners are up-regulated in resistant conditions relative to parental conditions. These gene-pairs are prime candidates for novel cross-talks contributing to lapatinib resistance. They associate EGFR/ErbB signaling with six other signaling pathways: Notch, Wnt, GPCR, hedgehog, insulin receptor/IGF1R and TGF-β receptor signaling. We conducted a literature survey to validate these cross-talks, and found evidence supporting a role for many of them in contributing to drug resistance. We also analyzed an independent study of lapatinib resistance in the BT474 breast cancer cell-line and found the same signaling pathways making cross-talks with the EGFR/ErbB signaling pathway as in the primary dataset. Conclusions: Our results indicate that the activation of compensatory pathways can potentially cause up-regulation of EGFR/ErbB pathway genes (counteracting the inhibiting effect of lapatinib) via signaling cross-talk. Thus, the up-regulated members of these compensatory pathways along with the members of the EGFR/ErbB signaling pathway are interesting as potential targets for designing novel anti-cancer therapeutics.

Getting stuck in local maxima is a problem that arises while learning Bayesian network (BN) structures. In this paper, we studied a recently proposed Markov chain Monte Carlo (MCMC) sampler, called the Neighbourhood sampler (NS), and examined how efficiently it can sample BNs when local maxima are present. We assume that a posterior distribution f (N, E|D) has been defined, where D represents data relevant to the inference, N and E are the set of nodes and directed edges, respectively. We illustrate the new approach by sampling from such a distribution, and inferring some BNs. The simulations conducted in this paper show that the new learning approach substantially avoids getting stuck in local modes of the distribution, and achieves a more rapid rate of convergence, compared to the MCMC Metropolis-Hastings sampler and other heuristic algorithms.

Many applications in graph analysis require a space of graphs or networks to be sampled uniformly at random. For example, one may need to efficiently draw a small representative sample of graphs from a particular large target space. We assume that a uniform distribution f (N, E) = 1/|X | has been defined, where N is a set of nodes, E is a set of edges, (N, E) is a graph in the target space X and |X | is the (finite) total number of graphs in the target space. We propose a new approach to sample graphs at random from such a distribution. The new approach uses a Markov chain Monte Carlo method called the Neighbourhood Sampler. We validate the new sampling technique by simulating from feasible spaces of directed or undirected graphs, and compare its computational efficiency with the conventional Metropolis-Hastings Sampler. The simulation results indicate efficient uniform sampling of the target spaces, and more rapid rate of convergence than Metropolis-Hastings Sampler.

Background: Initial success of inhibitors targeting oncogenes is often followed by tumor relapse due to acquired resistance. In addition to mutations in targeted oncogenes, signaling cross-talks among pathways play a vital role in such drug inefficacy. These include activation of compensatory pathways by other receptor tyrosine kinases, and altered activity of key effectors in cell survival and growthassociated pathways by other signaling pathways.

Background: Small molecule inhibitors, such as lapatinib, are effective treatments for breast cancer. Lapatinib typically produces early clinical benefits, but after prolonged use, tumours develop acquired resistance (AR). Recently, adaptive reprogramming of signaling circuitry was reported as a major cause of AR, hence maintaining sensitization of tumours to drug action is essential for durable growth inhibition.