Measuring and managing phenotypic heterogeneity and plasticity in breast cancer to improve therapeutic control Public Deposited

Our ability to therapeutically manage breast tumors has been revolutionized by the use of drugs targeting the activity of the estrogen and HER2 receptors. However, the efficacy of these treatments is restricted to tumors expressing/overexpressing these receptors, leaving the 18% of patients that lack ER and HER2 receptor expression minimal options for therapy. In particular, triple negative (TN) breast cancer patients are limited to a small set of chemotherapeutics for treatment options. Many small molecule kinase inhibitors are currently under clinical investigation for treatment of TN tumors, but despite targeting pathways shown to be commonly upregulated in this subtype, clinical success with these single agent targeted therapies has been poor. In this work we attempt to better understand the resistance mechanisms underlying the innate resistance of TN tumors to targeted kinase inhibitors. It is now widely appreciated that most tumors show intratumoral genomic heterogeneity due to a process of branched evolution. In this work we also demonstrate that triple negative tumors have high phenotypic heterogeneity, harboring multiple distinct cell states within a single tumor. Furthermore, we show that these tumor cell phenotypes are plastic, and cells can transition to drug-tolerant states upon therapeutic challenge with a wide range of targeted agents. This intratumoral heterogeneity and phenotypic plasticity likely supports the poor clinical successes of small molecule kinase inhibitor trials in TN patients. In order to improve future management of these tumors, we present two distinct therapeutic strategies that circumvent these resistance mechanisms and effectively kill heterogeneous triple negative breast cancers. This includes combination therapy using targeted therapeutics in combination with epigenetic reader protein inhibitors, or the use of pharmacological activators of Protein Phosphatase 2a (PP2A), both of which showed promising efficacy in heterogeneous breast cancers. These studies provide new tools to detect heterogeneous breast tumors and provide new therapeutic strategies to treat these aggressive cancers.

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