Dual Inhibition of PIM and PI3K Pathways: The Potential of IBL-302 in Breast Cancer Therapy

PI3K mutations are found in over 30% of breast cancers and are linked to resistance to trastuzumab, a HER2-targeting monoclonal antibody. PIM kinase expression is elevated in PI3K-treated breast cancer samples, suggesting it could be a key resistance pathway. IBL-302 is a novel dual-acting inhibitor of both PIM and PI3K signaling, which may offer significant therapeutic benefits for breast cancer.

In a preclinical evaluation, IBL-302 was tested on a panel of over 700 cancer cell lines, including 36 breast cancer cell lines categorized by clinical subtype. It showed significantly lower IC50 values in triple-negative breast cancer (TNBC) cell lines compared to HR+ and HER2+ cell lines. The sensitivity to IBL-302 was significantly correlated with PIM 1 and PIM 2 expression but not PIM 3.

HER2 is amplified or overexpressed in about 25% of breast cancers, promoting an aggressive phenotype through the PI3K/AKT pathway. IBL-302 demonstrated anti-proliferative effects in HER2+ breast cancer cell lines, including those with acquired resistance to trastuzumab or lapatinib. Notably, trastuzumab-resistant cell lines were more sensitive to IBL-302 than their parental counterparts. The combination of trastuzumab and IBL-302 significantly increased anti-proliferative effects in certain cell lines.

In vivo, IBL-302 treatment resulted in a significant reduction in tumor volume in a BALB/c nude mouse xenograft model with BT474 cells, without affecting body weight. These findings indicate that IBL-302 has in vitro efficacy across various breast cancer cell lines, including those resistant to trastuzumab. The in vivo single-agent efficacy in the BT474 xenograft model supports the potential of IBL-302 as a promising new treatment for breast cancer, particularly for HER2+ cells with trastuzumab resistance, warranting further clinical investigation.