Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R
Targeted therapies have significantly advanced breast cancer treatment, as demonstrated by the effectiveness of tamoxifen for hormone receptor-positive tumors and trastuzumab for HER2-positive tumors. However, triple-negative breast cancer (TNBC)—which lacks expression of these markers—has shown limited response to pathway-targeted therapies. Although many TNBCs rely on the PI3K pathway for growth and survival, PI3K inhibition alone has yielded modest clinical benefits.
To identify potential therapeutic combinations, we conducted an RNAi-based genetic screen in a human TNBC cell line to find kinases whose silencing enhances the efficacy of the PI3K inhibitor GDC-0941 (pictilisib). The screen revealed that knockdown of the insulin-like growth factor-1 receptor (IGF1R) significantly increased the cells’ sensitivity to GDC-0941. Supporting this finding, pharmacological inhibition of IGF1R with OSI-906 (linsitinib) exhibited strong synergy when combined with PI3K inhibition.
Further testing across a panel of 18 TNBC cell lines showed that this combination was synergistic in 8 lines. In these responsive lines, dual inhibition of PI3K and IGF1R led to greater suppression of downstream PI3K signaling compared to PI3K inhibition alone. Gene expression analysis suggested that IGF2BP3 expression levels may serve as a predictive biomarker for sensitivity to the combined PI3K/IGF1R blockade.
Overall, our findings indicate that co-targeting PI3K and IGF1R may offer a promising therapeutic strategy for a subset of TNBC patients.