IGF1R and MET Mediate Resistance to PI3K Inhibitors in Ovarian Cancer

The phosphoinositide-3-kinase, catalytic, alpha polypeptide gene (PIK3CA) is mutated or amplified in 30% of ovarian cancers. This gene encodes for p110α, the catalytic subunit of the class I PI3K. Many isoform specific inhibitors of p110α (p110αi), such as GDC0032, are currently being evaluated in clinical trials. These inhibitors show potent anti-tumor activity in cancer patients harboring PIK3CA mutations or amplifications. However, this positive response is limited, as tumors eventually develop resistance. Currently, the efficacy of p110αi in PIK3CA-mutated ovarian cancer is limited, as the molecular mechanisms underlying resistance to p110αi are unknown.

To unearth the molecular mechanisms of resistance to p110αi in PIK3CA-mutated ovarian cancer cell lines, we developed resistant ovarian cancer cell lines by chronically expose them to GDC0032. While GDC0032 induces cell cycle arrest and blocks the PI3K pathway downstream components AKT and mTOR in sensitive cells, resistant cells show reactivation of AKT and mTOR after 24 hours of treatment. shRNA re-sensitization screening showed involvement of some proteins in the GDC0032 resistance phenotype, namely IGF1R and MET, two important tyrosine kinase receptors. Validation of these results by pharmacological inhibitors and siRNAs showed that blockage of MET or IGF1R reverses sensitivity to GDC0032, and concomitantly deactivates AKT and mTOR in the presence of GDC0032.

Our study provides a rationale for targeting IGF1R or MET along with PI3K subunits in patients with ovarian tumors harboring PIK3CA-mutation or amplification.