A tipping-point for apoptosis following dual inhibition of HER2 signaling network by T-DM1 plus GDC-0980 maximizes anti-tumor efficacy
Abstract
HER2 signaling network and it is complex relationship using the PI3K-AKT-mTOR path explain the acquired potential to deal with anti-HER2 therapy noticed in clinics. Such complexity continues to be clinically apparent in the limited effectiveness of information within the BOLERO-1 and BOLERO-3 trials, which tested mixtures of trastuzumab (T), everolimus, and chemotherapy in females with HER2 advanced BC. Within the following MARIANNE trial also, a mix of T-DM1 plus pertuzumab delivered a non-inferior and yet not superior PFS when compared with trastuzumab along with a taxane. Algorithmic inhibition of PI3K/mTOR together with T or T-DM1 is, therefore, a beautiful drug combination, so we tested the mixture(s) in HER2 BC, particularly in T-resistant and PIK3CA mutated conditions. GDC-0980, a dual pan-PI3K/mTOR inhibitor alone or in conjunction with T or T-DM1, was examined inside a panel of HER2 T-sensitive (BT474, SKBR3), HER2 T-resistant (BT474HerR), HER2 /PIK3CA mutant (HCC1954, MDA-MB453), and HER2 /PTEN mutant (HCC1569) BC cell lines. GDC-0980 re-sensitized trastuzumab-resistant, PIK3CA mutant, or PTEN mutant cells to T and acted additively with T. Importantly, this activity was more when GDC-0980 is coupled with T-DM1. The mixture (with T or with T-DM1) ended up being tested within the HER2 /T-sensitive, HER2 /T-resistant, and HER2 /PIK3CA mutated BC xenograft models for that anti-tumor effect. And its anti-tumor effect, GDC-0980 effectively decreased tumor angiogenesis (CD31 staining). Maximum anti-tumor (from tumor growth inhibition to tumor regression) efficiency was noticed in the 3 xenograft models when T-DM1 was coupled with GDC-0980. The anti-proliferative results of GDC-0980 as evidenced with a decreased p-AKT (Ser473, The308), p-P70S6K, p-S6RP, and p-4EBP1, together with blockade of clonogenic 3D growth was supported through the initiation of apoptotic activity (annexin V, CASPASE3, cleaved PARP1 and mitochondrial depolarization) and it was considerably superior when GDC-0980 coupled with T-DM1. Interestingly, both trastuzumab and T-DM1 induce PD-L1 expression in HER2 amplified BC cells. Our data prove an oncogenic mutation of PIK3CA and HER2-amplification may represent biomarkers to recognize patients who will benefit most out of using GDC-0980 as well as an chance to incorporate immunotherapy within the mixture of anti-HER2 therapy.