Kindlin-1 Expression Is Associated With Egfr/Ras/Mapk Activation And Response To Mek Inhibitors In Triple-Negative Breast Cancer

Background: Triple-negative breast cancer (TNBC) accounts for ~15% of all invasive breast cancers. This heterogeneous group of tumors is the most aggressive and difficult-to-treat subtype of breast cancer. We previously demonstrated that Kindlin-1 is overexpressed in TNBC and patients with high Kindlin-1 have a worse prognosis. We determined that Kindlin-1 plays a major role in the epithelial to mesenchymal transition, tumor growth and breast cancer metastasis. TNBC have also been reported to express high levels of EGFR, in ~70% of the cases. Unfortunately, anti-EGFR therapy in TNBC fails to show a clinical benefit. In this study, we aimed to investigate a potential link between EGFR/RAS/MAPK pathway and Kindlin-1 in TNBC, and to propose new therapeutic strategies based on our findings. Methods: First, a gene set enrichment analysis was performed in 58 breast cancer cell lines (CCLE dataset) to detect the signaling pathways differentially enriched in cells expressing high levels of Kindlin-1. We next evaluated whether Kindlin-1 expression could be associated to an increased MAPK signaling by testing the mutational status and phosphorylation of key effectors of the pathway. To determine whether Kindlin-1 could be a predictive biomarker for the response to MEK inhibitors, we assessed its expression in sensitive versus resistant cell lines. Finally, we examined in vivo the anti-tumor efficacy of Selumetinib in a series of 27 triple negative breast cancer patient derived xenografts (PDX), highly representative of the originating tumor in terms of biology and therapeutic sensitivity. These PDX models have been characterized for Kindlin-1 expression (at RNA and protein levels). The sensitivity to MEKi of the TNBC PDX models was examined with regard to their Kindlin-1 expression. Results: Gene set enrichment analysis put in evidence that EGFR/RAS/MAPK pathway is upregulated in breast cancer cells with high Kindlin-1 expression. Although mutations are infrequent in breast cancer, an increased Kindlin-1 expression was observed in a subset of EGFR/RAS-activated cell lines (mutated or amplified). Moreover, TNBC expressing high levels of Kindlin-1 showed an increased phosphorylation of key effectors (ERK, MEK). We also demonstrated that Kindlin-1 mRNA expression was significantly increased in sensitive cell lines to different MEK inhibitors such as Trametinib (p=0.007) or Selumetinib (p=0.005) compared with resistant cells. In addition, in preclinical TNBC PDX models treated with Selumetinib there was a correlation between tumor growth inhibition and Kindlin-1 protein expression (r=0.57; p=0.017). Conclusion: Our findings indicate that Kindlin-1 expression may be a promising predictive biomarker of MEK inhibitors response in TNBC and may offer new therapeutic opportunities for patients with limited treatment options and refractory cancer types to current treatments. Citation Format: Paula Azorin, Florian Bonin, Zakia Tariq, Florence Coussy, Elisabetta Marangoni, Rosette Lidereau, Keltouma Driouch. Kindlin-1 expression is associated with EGFR/RAS/MAPK activation and response to MEK inhibitors in triple-negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3182.