3577 - The tyrosine kinase inhibitor Dasatinib blocks tumor growth, invasion and recurrence potential by interrupting the communication between cancer cells and their surrounding microenvironment in triple negative breast cancer

Background

Triple-negative breast cancer (TNBC) is the most aggressive among breast cancer subtypes, as these tumors frequently develop resistance to the treatment used. External signals provided by the surrounding tumor microenvironment (TM), which in mammary tumors is mainly constituted by adipose tissue (AT), control this resistance. Therefore, therapies that targets not only the cancer bulk but also its surrounding TM may be more effective. Preliminary in vitro and in vivo studies using mesenchymal stem cells from TNBC patient’s AT (MSC^TNBC) showed how a conditioned medium (CM) prepared from MSC^TNBC (MSC^TNBC-CM) promoted tumorigenicity, invasion, and chemoresistance. In the present work, molecular mechanism will be investigated to identify novel druggable targets in TNBC.

Methods

TNBC cells (MDA-MB-231, BT549, and HS578T) were exposed to MSC^TNBC-CM. The activation profile of tyrosine kinase receptors (RTKs) was evaluated using a commercial array. The effect of the inhibitors in the absence and presence of MSC^TNBC-CM on TNBC cells recurrence potential, invasion, and cell death were evaluated in vitro through clonogenic, matrix invasion, and flow cytometry assays. Impact on tumour growth was evaluated in a MSC^TNBC-TNBC preclinical model (BALB-nu mice).

Results

RTKs activation profile in response to MSC^TNBC-CM revealed that TM secreted factors activates Src protein family (SFK) in TNBC. The use of the SFK inhibitor Dasatinib, both in vitro and in vivo, showed a marked reduction of invasion and recurrence potential, an induction of cell death, and a lower of tumour growth.

Conclusions

In this study, we describe SFK as mediators in the communication within the tumour adipose niche and provides fundamental information to understand TNBC progression, as well as its behavior in response to chemotherapy. The specific blockade of the SFK signaling pathway with Dasatinib can interrupt this communication and revert TM protective effect, resulting in death and smaller tumour size. Our results open the gate to the development of new strategies targeting TM to treat TNBC patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Diputación de Albacete.

Disclosure

All authors have declared no conflicts of interest.