Project description:Triple negative breast cancer (TNBC) is a heterogeneous disease with limited therapeutic options. Two commonalities of TNBCs are a failure to express receptors for hormone or HER2-targeted therapies and high levels of chromosomal instability (CIN), both of which generate considerable therapeutic challenges. Focusing on the Src Family Kinases (SFKs), we found that treatment of TNBC cells with pan-SFK inhibitors causes abnormal nuclear phenotypes and DNA double strand breaks that are characteristic of excessive CIN, suggesting that SFKs may provide a vulnerability for treating TNBC. While prior clinical studies found that pan-SFK inhibition causes dose-limiting toxicities and minimal efficacy, we asked whether targeting individual family members may provide more specificity and hence, greater impact. Analysis of public datasets revealed that YES1 is one of the most highly expressed SFKs in basal/TNBC breast cancer and that its expression is associated with poor patient outcomes. Genomic and pharmacologic targeting of YES1 in TNBC cells further demonstrated that its sustained activity is essential for normal mitoses, including centrosome composition and bipolar spindle formation, as well as chromosome stability. We then determined if the ability of YES1 inhibition to induce mitotic defects and profound CIN could be leveraged to potentiate the efficacy of taxanes, cornerstone drugs for TNBC that also induce CIN. Combining paclitaxel with the selective YES1 inhibitor, CH695355, synergistically inhibited growth of several TNBC models both in vitro and in vivo. Moreover, YES1 inhibition re-sensitized taxane-resistant TNBC cells to paclitaxel. Elevated tumor expression of YES1 was also associated with worse overall survival of TNBC patients treated with combined taxanes/anthracyclines. Mechanistically, YES1 suppression leads to a loss of FOXM1 expression, a transcription factor whose disruption has also been reported to induce CIN, but has not yet been effectively therapeutically targeted. Together, these studies demonstrate that the SFK family member, YES1, is a novel and essential regulator of genome stability in TNBC. More broadly, these results suggest that YES1 may be a therapeutically targetable vulnerability that could potentiate the efficacy of mitotic inhibitors to induce maladaptive CIN and improve the treatment of TNBC.

Project description:Breast cancer is a heterogeneous collection of disease arising from the breast with distinct molecular and phenotypic features. Certain subsets of patients have tumors that are particularly difficult-to-treat, which include triple-negative breast cancer (TNBC), metastatic/recurrent disease and rare histological variants. To delineate the underlying biology and identify therapeutic candidates for these patients, a series of 37 breast cancer patient-derived xenografts (PDX) from both chemo-naïve and pre-treated specimens was generated from 81 transplant attempts. Whole-genome and transcriptome sequencing revealed marked fidelity of the molecular landscape for the majority of PDXs in comparison to parental tumors. Reverse-phase protein array analysis of PDXs further identified potential therapeutic targets. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases was the most common pattern of dissemination and observed in 34.5% of models. Three PDXs recapitulated the metastatic localization seen in the corresponding patients, including two lines with high-frequency metastases to multiple vital organ systems, while another PDX displayed tropism to the skull-base. Chemosensitivity profiling was performed in vivo with standard-of-care agents (doxorubicin, cisplatin, gemcitabine or paclitaxel), where multi-drug chemoresistance was found in 60.0% of PDXs and 64.7% of responses were concordant with pre-engraftment responses observed in the patient. Consolidating chemogenomic data identified potentially actionable features in 97.2% of PDXs, and marked regressions were seen in vivo when a subset of these underwent proof-of-concept functional studies. This included FGFR inhibitor sensitivity in a FGFR1-amplified lobular carcinoma, mTOR inhibitor sensitivity in a recurrent neuroendocrine breast cancer with proteomic evidence of mTOR/PI3K activation, and platinum sensitivity in a TNBC with BRCA1 germline mutation predicted as benign. Together, this clinically-annotated PDX library with comprehensive molecular and phenotypic profiling serves as a resource for both discovery and validation preclinical studies on difficult-to-treat breast tumors.

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Identification of Src Family Kinases as potential therapeutic targets for chemotherapy-resistant triple negative breast cancer

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