Dataset Information

How Compensatory Mechanisms and Adaptive Rewiring Have Shaped Our Understanding of Therapeutic Resistance in Cancer.

ABSTRACT: Therapeutic resistance to targeted therapies by tumor cells is a common and serious problem in the clinic. Increased understanding of the molecular mechanisms that underly resistance is necessary for the rational design and improvement of effective pharmacologic treatment strategies. The landmark study by O'Reilly and colleagues published in Cancer Research in 2006 provided valuable insights into nongenomic adaptive rewiring and compensatory mechanisms responsible for mediating resistance to targeted inhibition of the PI3K-AKT-mTOR pathway, and how tumor cells regulate signaling pathways via negative feedback loops. These findings have proven fundamental for guiding current efforts to develop effective combination treatments and provided a blueprint for research studies aimed at understanding the intricacies of cellular signaling.See related article by O'Reilly and colleagues, Cancer Res 2006;66:1500-8.

SUBMITTER: Bergholz JS

PROVIDER: S-EPMC9033251 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

How Compensatory Mechanisms and Adaptive Rewiring Have Shaped Our Understanding of Therapeutic Resistance in Cancer.

Bergholz Johann S JS Zhao Jean J JJ

Cancer research 20211201 24

Therapeutic resistance to targeted therapies by tumor cells is a common and serious problem in the clinic. Increased understanding of the molecular mechanisms that underly resistance is necessary for the rational design and improvement of effective pharmacologic treatment strategies. The landmark study by O'Reilly and colleagues published in <i>Cancer Research</i> in 2006 provided valuable insights into nongenomic adaptive rewiring and compensatory mechanisms responsible for mediating resistance ...[more]

PMID: 34911779

Similar Datasets

Project description: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 p1-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 metastasis 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.

Dataset Information

How Compensatory Mechanisms and Adaptive Rewiring Have Shaped Our Understanding of Therapeutic Resistance in Cancer.

Publications

How Compensatory Mechanisms and Adaptive Rewiring Have Shaped Our Understanding of Therapeutic Resistance in Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets