Targeting a cell state common to triple‐negative breast cancers

Abstract

Some mutations in cancer cells can be exploited for therapeutic intervention. However, for many cancer subtypes, including triple-negative breast cancer (TNBC), no frequently recurring aberrations could be identified to make such an approach clinically feasible. Characterized by a highly heterogeneous mutational landscape with few common features, many TNBCs cluster together based on their ‘basal-like’ transcriptional profiles. We therefore hypothesized that targeting TNBC cells on a systems level by exploiting the transcriptional cell state might be a viable strategy to find novel therapies for this highly aggressive disease. We performed a large-scale chemical genetic screen and identified a group of compounds related to the drug PKC412 (midostaurin). PKC412 induced apoptosis in a subset of TNBC cells enriched for the basal-like subtype and inhibited tumor growth in vivo. We employed a multi-omics approach and computational modeling to address the mechanism of action and identified spleen tyrosine kinase (SYK) as a novel and unexpected target in TNBC. Quantitative phosphoproteomics revealed that SYK inhibition abrogates signaling to STAT3, explaining the selectivity for basal-like breast cancer cells. This non-oncogene addiction suggests that chemical SYK inhibition may be beneficial for a specific subset of TNBC patients and demonstrates that targeting cell states could be a viable strategy to discover novel treatment strategies.

STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation

“…In our study specifically, it is clear that glucocorticoid induction of GR leads to increased cell proliferation in basal-like breast cancer cell lines and patient-derived organoids. It also leads to increased expression of genes that are cooperatively regulated by STAT3, a known promoter of cancer growth and invasion (53)(54)(55)(56)(57)(58). Recently, clinical trials have been initiated to test whether inhibiting GR directly with mifepristone or by inhibiting its chaperone, Hsp90, will enhance the efficacy of chemotherapy in basal-like breast cancer (16,59).…”

Pharmacological and immunological targeting of tumor mesenchymalization

“…Midostaurin is a derivative of the natural alkaloid staurosporine, a broad-spectrum kinase inhibitor, and it is being investigated in several clinical trials for leukemia and a phase I trial in combination with radiation and chemotherapy for advanced rectal cancer (NCT01282502). Additional studies with midostaurin demonstrated selective cytotoxicity in other tumor models of mesenchymalization, including in cells treated with TGF-β, in mesenchymal-like tumor xenograft explants, in TNBC cell lines, and in a TNBC patient-derived xenograft (Muellner et al , 2015). Target analysis revealed that midostaurin inhibits both Aurora kinase A (AURKA), a target previously implicated in basal-like breast cancer (Staff et al, 2010), and spleen tyrosine kinase (SYK), a critical mediator of immune receptor signaling (Turner et al, 2000) that was previously unrecognized in TNBC pathology.…”

“…Using an isogenic MCF10A cell line model with ectopic expression of the transcription factor TWIST, a driver of mesenchymalization, a library of 20,000 chemicals was screened and identified midostaurin (PKC412) as a selectively toxic compound in mesenchymalized tumor cells (Muellner et al, 2015). Midostaurin is a derivative of the natural alkaloid staurosporine, a broad-spectrum kinase inhibitor, and it is being investigated in several clinical trials for leukemia and a phase I trial in combination with radiation and chemotherapy for advanced rectal cancer (NCT01282502).…”

“…Target analysis revealed that midostaurin inhibits both Aurora kinase A (AURKA), a target previously implicated in basal-like breast cancer (Staff et al, 2010), and spleen tyrosine kinase (SYK), a critical mediator of immune receptor signaling (Turner et al, 2000) that was previously unrecognized in TNBC pathology. SYK inhibition was found to abrogate signaling by STAT3, a pathway known to be associated with CSC features in breast cancer (Marotta et al, 2011), and also synergized with inhibition of AURKA, showing that the multiple targets of midostaurin can be targeted in combination to kill mesenchymal, basal-like breast tumor cells (Muellner et al , 2015). …”

Emerging therapies for acute myeloid leukemia: translating biology into the clinic

“…While lower potency, these metabolites are found at higher levels in plasma and appear to contribute significantly to midostaurin's activity (41). Studies in breast cancer (42) and systemic mastocytosis (43) have identified SYK as a target of midostaurin. The relative contribution of SYK inhibition remains unclear, but given that SYK is an independent therapeutic target (44), beneficial off-target effects are likely.…”