Abstract 3577
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 (MSCTNBC) showed how a conditioned medium (CM) prepared from MSCTNBC (MSCTNBC-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 MSCTNBC-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 MSCTNBC-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 MSCTNBC-TNBC preclinical model (BALB-nu mice).
Results
RTKs activation profile in response to MSCTNBC-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.
Resources from the same session
1267 - Genetic landscape of KEAP1 and NFE2L2 mutated cancers from the AACR GENIE database
Presenter: Mark Zaki
Session: Poster Display session 1
Resources:
Abstract
878 - β-arrestin1 is involved in the Ras-induced malignant transformation
Presenter: Takashi Shibano
Session: Poster Display session 1
Resources:
Abstract
4143 - Incidence of second cancer among PLWHIV: retrospective observational study of a series of 601 patients in the French CANCERVIH network
Presenter: Jean-Philippe Spano
Session: Poster Display session 1
Resources:
Abstract
5145 - A challenging task – Identifying carcinoma of unknown primary (CUP) patients according to ESMO guidelines: the CUPISCO trial experience
Presenter: Chantal Pauli
Session: Poster Display session 1
Resources:
Abstract
1737 - Incidence and Outcome of chronic lymphocytic leukemia with Deletion 17p: An Indian experience; challenges and opportunities
Presenter: Ajay Gogia
Session: Poster Display session 1
Resources:
Abstract
2596 - Driving solo? Investigation into collaborating mutations in SDH-deficient neoplasia
Presenter: Jonathan Killian
Session: Poster Display session 1
Resources:
Abstract
1499 - The potential of a novel antiangiogenic VEGFR1-D2 binding peptide in oncology therapeutics
Presenter: Afsaneh Sadre Momtaz
Session: Poster Display session 1
Resources:
Abstract
1775 - First-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumors
Presenter: Mayu Yunokawa
Session: Poster Display session 1
Resources:
Abstract
4584 - First-in-human study of ABBV-621 in patients (pts) with previously treated sold tumors: Dose-optimization cohorts
Presenter: Emiliano Calvo
Session: Poster Display session 1
Resources:
Abstract
3620 - Safety, efficacy, PK and PD biomarker results of the first-in-human study of mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor BAY 1436032 in patients (pts) with mIDH1 advanced solid tumours
Presenter: Wolfgang Wick
Session: Poster Display session 1
Resources:
Abstract