Abstract P50: IQGAP1-YAP-IQGAP2 Axis: Modulators Of Stemness, Resistance And Relapse Dynamics

Abstract

Breast cancer continues to be the foremost cause of cancer-related deaths among women, driven by high rates of therapy resistance and relapse, largely due to the persistence of cancer stem cells (CSCs). Despite advances in targeted therapies, the ERK signalling pathway remains a major contributor to drug resistance, demanding the discovery of novel regulatory mechanisms to overcome this barrier. In this study, we uncover a previously underappreciated regulatory axis involving the IQGAP family proteins, where IQGAP1 promotes stemness and oncogenic signalling, while IQGAP2 functions as a potent tumour suppressor, capable of restraining CSC properties. Through integrative analysis of TCGA Firehose data, we identified a significant downregulation of IQGAP2 in breast cancer, with enrichment of pathways linked to stemness and therapy resistance, including Hippo, Wnt, and ERK signalling. Using functional assays, flow cytometry, and in vivo xenograft models, we demonstrate that IQGAP2 overexpression dramatically suppresses CSC traits, including reduced spheroid formation and CD44:CD24 ratio, along with downregulation of key stemness markers (OCT4, SOX2, NANOG). Most critically, we show that IQGAP2 disrupts the oncogenic IQGAP1-YAP interaction, leading to the attenuation of YAP-driven ERK hyperactivation—a mechanism often responsible for bypassing therapeutic inhibition. Strikingly, re-expression of IQGAP1 in the IQGAP2-overexpressing background restores ERK activity and rescues the stem-like phenotype, providing direct functional evidence of the IQGAP2–YAP–IQGAP1 axis as a master regulator of stemness and resistance. Our findings establish IQGAP2 not just as a biomarker, but as a functional barrier to ERK-mediated resistance, opening new avenues for combination therapies targeting the YAP-ERK interface. In summary, this work reveals a critical molecular switch that determines cancer cell fate and therapeutic response, and highlights IQGAP2 restoration as a promising strategy to dismantle ERK-driven resistance and eliminate breast cancer stemness at its root.