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  • br Significance Cellular heterogeneity for phenotypic featur

    2021-10-21


    Significance Cellular heterogeneity for phenotypic features is a key mechanism underlying disease progression and therapeutic resistance, yet its regulation is poorly understood at the molecular level. Our findings demonstrate that endocrine resistance is associated with higher transcriptomic heterogeneity and provide proof of principle for how decreasing cellular transcriptomic heterogeneity by modulating the activity of epigenetic enzymes, such as KDM5 family members, can lead to improved responses to treatment. We also present conclusive evidence that acquired resistance to anti-estrogens and KDM5 inhibitors is mechanistically distinct; although both involve gain of estrogen-independent growth. These observations suggest that epigenetic agents may improve the efficacy of cancer therapies when used in combination, even when they have limited activity as single agents.
    Introduction Modulation of Ciclopirox Ciclopirox structure due to post-translational modification of histones plays a key role in establishing cell-type-specific gene expression patterns, and alterations of this process are involved in tumorigenesis (Flavahan et al., 2017). Frequent mutations of genes encoding for chromatin-modifying enzymes and histones in multiple human cancer types further emphasize the role of perturbed epigenetic programs in tumor evolution (Feinberg et al., 2016). However, the functional consequences of these mutations remain relatively poorly characterized. In breast cancer, epigenetic regulators and transcription factors are among the most frequently mutated genes, especially in luminal tumors (Cancer Genome Atlas Network, 2012). More recent sequencing of endocrine-resistant metastatic breast tumors has identified alterations previously not detected in primary tumors, such as ESR1 mutations in a subset of cases (Jeselsohn et al., 2015). Most of these ESR1 mutations occur in the ligand-binding domain (e.g., ESR1Y537S) and confer decreased sensitivity to anti-estrogens such as fulvestrant and tamoxifen. The majority (∼70%) of breast cancer patients are diagnosed with estrogen receptor-positive (ER+) hormone-dependent tumors and many progress to treatment-resistant metastatic disease. Therefore, a better understanding of the mechanisms of endocrine resistance and identification of strategies to decrease or prevent it would have high clinical impact. We previously reported that KDM5B, encoding a histone H3 lysine 4 (H3K4) demethylase, is an oncogene in luminal ER+ breast cancer due to its frequent amplification and overexpression, and its higher activity being associated with shorter disease-free survival in breast cancer patients treated with endocrine therapy (Yamamoto et al., 2014). KDM5B was also identified as a gene required for tumor maintenance in melanoma (Roesch et al., 2010), and its increased expression is associated with resistance to BRAF inhibitors and chemotherapy (Roesch et al., 2013). Other KDM5 family members such as KDM5A have also been implicated in therapeutic resistance in lung and other cancer types (Sharma et al., 2010), triggering an interest in developing KDM5 inhibitors (KDM5i) for cancer treatment (Horton et al., 2016, Johansson et al., 2016, Vinogradova et al., 2016). However, the mechanisms by which the KDM5 family of histone demethylases (HDMs) contribute to tumorigenesis and therapy resistance remains poorly defined.
    Results
    Discussion Hormone-dependent ER+ luminal tumors constitute the most common subtype representing ∼70% of all breast cancer cases. Although endocrine therapies are effective for the treatment of both early and advanced-stage disease, inherent and acquired resistance is a major clinical challenge (Osborne and Schiff, 2011). Numerous mechanisms have been proposed to explain endocrine resistance including changes in ER regulators and growth factor signaling pathways (Musgrove and Sutherland, 2009, Osborne and Schiff, 2011). Exome sequencing of metastatic lesions in endocrine-resistant disease identified ESR1 mutations, implying that genetic alterations are likely to be responsible for resistance in a subset of cases (Jeselsohn et al., 2017). We have previously shown that a high KDM5B PARADIGM (Vaske et al., 2010) activity score is associated with shorter disease-specific survival in endocrine therapy-treated ER+ breast cancer patients, implicating KDM5B in endocrine resistance (Yamamoto et al., 2014). Here we describe a comprehensive characterization of mechanisms of response and resistance to KDM5 inhibitors and their relevance for endocrine sensitivity. We found that inhibition of KDM5B and KDM5A increases sensitivity to fulvestrant in both hormone-sensitive and endocrine-resistant cells. Single-cell analysis of drug-sensitive and resistant populations using inDrop and CyTOF as well as lentiviral barcoding confirmed that endocrine resistance is due to the selection for a pre-existing distinct cell population.