The Tyrosine Kinome Dictates Breast Cancer Heterogeneity and Therapeutic Responsiveness

Abstract

Phospho-tyrosine signaling networks control numerous biological processes including cellular differentiation, cell growth and survival, motility, and invasion. Aberrant regulation of the tyrosine kinome is a hallmark of malignancy and influences all stages of breast cancer progression, from initiation to the development of metastatic disease. The success of specific tyrosine kinase inhibitors strongly validates the clinical relevance of tyrosine phosphorylation networks in breast cancer pathology. However, a significant degree of redundancy exists within the tyrosine kinome. Numerous receptor and cytoplasmic tyrosine kinases converge on a core set of signaling regulators, including adaptor proteins and tyrosine phosphatases, to amplify pro-tumorigenic signal transduction pathways. Mutational activation, amplification, or overexpression of one or more components of the tyrosine kinome represents key contributing events responsible for the tumor heterogeneity that is observed in breast cancers. It is this molecular heterogeneity that has become the most significant barrier to durable clinical responses due to the development of therapeutic resistance. This review focuses on recent literature that supports a prominent role for specific components of the tyrosine kinome in the emergence of unique breast cancer subtypes and in shaping breast cancer plasticity, sensitivity to targeted therapies, and the eventual emergence of acquired resistance. J. Cell. Biochem. 117: 1971-1990, 2016. © 2016 Wiley Periodicals, Inc.

Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer

“…Although the kinases that phosphorylate these residues in TMEM16A have not been identified, the phosphorylation-dependent regulation of TMEM16A’s interaction with other proteins suggests that the role of TMEM16A may be dependent on the kinase-related signaling in certain cancer cells. It is well known that protein kinases that regulate cell proliferation are dysregulated in cancer and exhibit cell-specific heterogeneity [ 103 , 104 ]. Therefore, the cell-specific role of TMEM16A may be the result of kinase heterogeneity in different cancer cells.…”

The Shc1 adaptor simultaneously balances Stat1 and Stat3 activity to promote breast cancer immune suppression

“…Finally, the FAK tyrosine kinase regulates transcriptional responses that block anti-tumour immunity16. An important caveat that may limit the efficacy of tyrosine kinase inhibitors in augmenting tumoricidal immune responses is the inherent functional redundancy within the tyrosine kinome, leading to the emergence of therapeutic resistance17.…”

New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome

“…However, such approaches can result in relatively poor sampling of the phospho-tyrosine (pTyr) pool; therefore, anti-pTyr antibody-based enrichment is typically employed to evaluate this less abundant modification (47). Effective sampling of this subset is particularly important given the dominant role of tyrosine kinases in controlling early events in signaling that are frequently dysregulated in diseases such as cancer (48,49). An important technical challenge will be the development of advanced analytic approaches to sample the extent and positional distribution of acid-labile, rare, substoichiometric and combinatorial phosphorylation in human cells.…”