Rationale-based therapeutic combinations with PI3K inhibitors in cancer treatment.
The PI3K/AKT/mTOR signaling is important for cell proliferation, survival, and metabolism. Hyperactivation of this pathway is one of the most common signaling abnormalities observed in cancer and a substantial effort has recently been made to develop molecules targeting this signaling cascade. However, it is becoming evident that PI3K inhibitors used as single agents do not elicit dramatic or durable responses. Given the numerous mechanisms mediating intrinsic and acquired resistance to these agents, hypothesis-based combinatorial strategies are probably needed to fully exploit their antitumor activity. In the first part of this review, we briefly dissect the PI3K/AKT/mTOR axis and list the most advanced compounds targeting different nodes of this cascade. The second part focuses on what we believe to be the most promising rationale-based therapeutic combinations with PI3K/AKT/mTOR inhibitors in solid tumors, with special emphasis on breast cancer.
Human Oncology & Pathogenesis Program (HOPP); Memorial Sloan Kettering Cancer Center ; New York, NY USA.
Pau
P
Castel
Human Oncology & Pathogenesis Program (HOPP); Memorial Sloan Kettering Cancer Center ; New York, NY USA.
Eneda
E
Toska
Human Oncology & Pathogenesis Program (HOPP); Memorial Sloan Kettering Cancer Center ; New York, NY USA.
Zachary S
ZS
Zumsteg
Human Oncology & Pathogenesis Program (HOPP); Memorial Sloan Kettering Cancer Center ; New York, NY USA.
F Javier
FJ
Carmona
Human Oncology & Pathogenesis Program (HOPP); Memorial Sloan Kettering Cancer Center ; New York, NY USA.
Moshe
M
Elkabets
Human Oncology & Pathogenesis Program (HOPP); Memorial Sloan Kettering Cancer Center ; New York, NY USA.
Ana
A
Bosch
Human Oncology & Pathogenesis Program (HOPP); Memorial Sloan Kettering Cancer Center ; New York, NY USA.
Maurizio
M
Scaltriti
AKT; PIK3CA; PTEN; resistance; targeted therapy