Dasatinib in breast cancer: Src-ing for response in all the wrong kinases

Kennedy, Laura C.; Gadi, Vijayakrishna

doi:10.21037/atm.2018.10.26

Cited by 17 publications

(12 citation statements)

References 22 publications

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“…12 Additionally, clinical trials of dasatinib in combination with other chemotherapy or targeted agents for TNBC have been generally unimpressive. 27,28 Consistent with the clinical failure of dasatinib monotherapy, our data indicated that dasatinib by itself failed to induce significant cytotoxicity at the clinically achievable and tolerable concentrations of <100 nM. Therefore, it may be that the lack of efficacy is in part due to lack of cancer cell killing at the doses achievable in humans.…”

Section: Discussionsupporting

confidence: 70%

Identification of a Triple Drug Combination That Is Synergistically Cytotoxic for Triple-Negative Breast Cancer Cells Using a Novel Combination Discovery Approach

Ahmad

Williams

et al. 2020

SLAS Discovery

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Triple-negative breast cancer (TNBC) is a very aggressive form of breast cancer with few molecularly targeted therapies. We used a novel unbiased approach to identify higher-order synergistic or enhancer combinations of marketed kinase inhibitor drugs that inhibit cell viability of TNBC cell lines. We mixed all 33 kinase-targeted drugs on the market at the time of this study, which allowed for all possible combinations to exist in the initial mixture. A kinase inhibitor group dropout approach was used to identify active groups and then single active drugs. After only three rounds of deconvolution, we identified five single drugs to test further. After further testing, we focused on one novel subset consisting of three kinase inhibitor drugs: dasatinib, afatinib, and trametinib (DAT) that target src family kinases, HER2/EGFR, and MEK, respectively. The DAT combination potently inhibited the proliferation of three TNBC cell lines and modestly inhibited a fourth. However, it was not significantly more potent or synergistic than other two drug combinations of these drugs. The cytotoxic activities of all possible combinations of these three drugs were also analyzed. Compared with all two-way combinations, the three-way DAT combination generated the most cytotoxicity and the highest synergies for two of the four cell lines tested, with possibly mild synergy in a third cell line. These data indicated that the DAT combination should be evaluated for efficacy in an in vivo model of TNBC and may provide a novel combination of existing drugs for the treatment of a subset of TNBC cases.

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Section: Discussionsupporting

confidence: 70%

Identification of a Triple Drug Combination That Is Synergistically Cytotoxic for Triple-Negative Breast Cancer Cells Using a Novel Combination Discovery Approach

Ahmad

Williams

et al. 2020

SLAS Discovery

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“…While modest HER2 protein expression (IHC 1+ or 2+) can be detected in 60% of luminal breast cancer [49], HER2 inhibitors are generally not indicated in these tumors. While SRC has been reported to play a key role in breast cancer bone metastasis and hormonal therapy resistance [50][51][52], the clinical trials of SRC inhibitors in unselected metastatic breast cancer patients have been disappointing [50]. Our in vitro therapeutic studies on the T47D, HCC1428, and ZR-75-1 models suggest that the patients may be treated with HER2 and/or SRC inhibitors in combination with endocrine therapy depending on the context of HER2 and SRC expression levels.…”

Section: Ectopic Expression Of the Esr1-ccdc170 Fusion Variants Promomentioning

confidence: 93%

Therapeutic role of recurrent ESR1-CCDC170 gene fusions in breast cancer endocrine resistance

Veeraraghavan

et al. 2020

Preprint

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Background: Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance have not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized. Methods:The endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays. Results:Our results suggested that different ESR1-CCDC170 fusions endow different levels of reduced endocrine sensitivity in vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling.Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib.Conclusion: ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors. BackgroundEndocrine therapy is the most effective treatment for estrogen-receptor (ER)-positive breast cancer (also known as luminal breast cancer). Agents targeting ER, including selective ER modulators (SERMs, i.e. Tamoxifen), selective ER down-regulators (SERDs, i.e. Fulvestrant) and aromatase inhibitors (AIs, i.e. letrozole) are the mainstays of treatment [1]. However, the efficacy of endocrine therapy is limited by intrinsic and acquired endocrine resistance [2]. About a quarter of the patients with primary tumor and almost all patients with metastases will present with or eventually develop endocrine resistance [3]. Tremendous efforts have been made to study the mechanism of endocrine resistance, and emerging evidence suggests that ESR1 mutations or fusions that mutate or eliminate its ligand binding domain constitute one of the most important driving mechanisms [3][4][5][6].Recurrent gene fusions resulting from chromosome t...

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“…However, perioperative bosutinib was not shown to have an anti-metastatic effect in our model. This may not be entirely surprising, given that standard treatment with bosutinib requires weeks in order to achieve a clinical effect, and as previously mentioned, in clinical settings breast cancer is not highly responsive to bosutinib [24,27]. If lidocaine does act via Src inhibition in reducing metastasis then it would be reasonable to expect that co-treatment with bosutinib would result in additive effects leading to greater reduction of lung metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…To examine this, we used bosutinib (SKI-606)—an Src/Bcr-Abl tyrosine kinase inhibitor used to treat haematological malignancies [23]. Bosutinib has been assessed in breast cancer treatment clinical trials, with largely disappointing results [24]. Although bosutinib’s action is not entirely isolated to Src inhibition, it is more selective than similar agents such as dasatinib which also target a range of cancer-implicated enzymes such as c-KIT [25].…”

Section: Discussionmentioning

confidence: 99%

Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery

Wall

Crowley

Sherwin

et al. 2019

Cancers

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Breast cancer recurs in 20% of patients following intended curative resection. In vitro data indicates that amide local anaesthetics, including lidocaine, inhibit cancer cell metastasis by inhibiting the tyrosine kinase enzyme Src. In a murine breast cancer surgery model, systemic lidocaine reduces postoperative pulmonary metastases. We investigated whether the additional administration of bosutinib (a known Src inhibitor) influences lidocaine’s observed beneficial effect in this in vivo model. Female BALB/c mice (n = 95) were inoculated with 25,000 4T1 cells into the mammary fad pad and after 7 days the resulting tumours were excised under sevoflurane anaesthesia. Experimental animals were randomized to one of four treatments administered intravenously prior to excision: lidocaine, bosutinib, both lidocaine and bosutinib in combination, or saline. Animals were euthanized 14 days post-surgery and lung and liver metastatic colonies were evaluated. Post-mortem serum was analysed for MMP-2 and MMP-9, pro-metastatic enzymes whose expression is influenced by the Src pathway. Lidocaine reduced lung, but not liver metastatic colonies versus sevoflurane alone (p = 0.041), but bosutinib alone had no metastasis-inhibiting effect. When combined with lidocaine, bosutinib reversed the anti-metastatic effect observed with lidocaine on sevoflurane anaesthesia. Only lidocaine alone reduced MMP-2 versus sevoflurane (p = 0.044). Both bosutinib (p = 0.001) and bosutinib/lidocaine combined (p = 0.001) reduced MMP-9 versus sevoflurane, whereas lidocaine alone did not. In a murine surgical breast cancer model, the anti-metastatic effects of lidocaine under sevoflurane anaesthesia are abolished by the Src inhibitor bosutinib, and lidocaine reduces serum MMP-2. These results suggest that lidocaine may act, at least partly, via an inhibitory effect on MMP-2 expression to reduce pulmonary metastasis, but whether this is due to an effect on Src or via another pathway remains unclear.

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Dasatinib in breast cancer: Src-ing for response in all the wrong kinases

Cited by 17 publications

References 22 publications

Identification of a Triple Drug Combination That Is Synergistically Cytotoxic for Triple-Negative Breast Cancer Cells Using a Novel Combination Discovery Approach

Identification of a Triple Drug Combination That Is Synergistically Cytotoxic for Triple-Negative Breast Cancer Cells Using a Novel Combination Discovery Approach

Therapeutic role of recurrent ESR1-CCDC170 gene fusions in breast cancer endocrine resistance

Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery

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