IL-8 secreted by tumor associated macrophages contribute to lapatinib resistance in HER2-positive locally advanced breast cancer via activation of Src/STAT3/ERK1/2-mediated EGFR signaling

• Published in: Biochimica et biophysica acta. Molecular cell research 2021-05, Vol.1868 (6), p.118995-118995, Article 118995
• Main Authors: Ahmed, Shaza, Mohamed, Hossam Taha, El-Husseiny, Noura, El Mahdy, Manal M., Safwat, Gehan, Diab, Ayman A., El-Sherif, Ahmed A., El-Shinawi, Mohamed, Mohamed, Mona Mostafa
• Format: Article
• Language: English
• Subjects: EGFR; HER2; Locally advanced breast cancer; Src; STAT3 and Erk1/2; Tumor associated macrophages
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2021.118995

Locally advanced breast cancer (LABC) is an aggressive disease characterized by late clinical presentation, large tumor size, treatment resistance and low survival rate. Expression of EGFR/HER2 and activation of intracellular tyrosine kinase domains in LABC are associated with poor prognosis. Thus, target therapies such as the anti-receptor tyrosine kinases lapatinib drug have been more developed in the past decade. The response to lapatinib involves the inhibition of RTKs and subsequently signaling molecules such as Src/STAT3/Erk1/2 known also to be activated by the cytokines in the tumor microenvironment (TME). The aim of the present study is to identify the major cytokine that might contribute to lapatinib resistance in EGFR+/HER2+ LABC patients. Indeed, tumor associated macrophages (TAMs) are the main source of cytokines in the TME. Herein, we isolated TAMs from LABC during modified radical mastectomy (MRM). Cytokine profile of TAMs revealed that IL-8 is the most prominent highly secreted cytokine by TAMs of LABC patients. Using in-vitro cell culture model we showed that recombinant IL-8 (50 and 100 ng/mL) at different time intervals interfere with lapatinib action via activation of Src/EGFR and signaling molecules known to be inhibited during treatment. We proposed that to improve LABC patients' response to lapatinib treatment it is preferred to use combined therapy that neutralize or block the action of IL-8. [Display omitted] •HER2+ LABC patients showed high resistance to target therapy RTKs (lapatinib).•Previous studies showed that IL-8 mediates resistance RTKs target therapy.•We found that IL-8 is highly secreted cytokine by TAMs of HER2+ LABC patients.•IL-8 interfere with lapatinib action by activating EGFR downstream signaling molecules.•Inhibiting IL-8 by monoclonal antibody during Lapatinib treatment is essential.