Title:PI3K Pathway Inhibitors: Better Not Left Alone
Volume: 19
Issue: 5
Author(s): Ben Markman, Jessica J. Tao and Maurizio Scaltriti
Affiliation:
Keywords:
PI3K, PIK3CA, PTEN, mTOR, Akt, PI3K inhibitor, therapeutic combination, clinical trial, signaling pathway, tumor suppressor
Abstract: The PI3K/Akt/mTOR signaling pathway plays a key role in diverse physiologic processes. It is also central to many aspects of
the malignant process. Genetic phenomena that lead to constitutive pathway activation are common in human cancer; the most relevant
are mutations affecting the catalytic subunit of PI3K and loss of function of the PTEN tumor suppressor. These factors have made this
important cascade attractive as a potential target for cancer therapeutics. A host of inhibitors are now in various stages of development
that target key nodes within the PI3K pathway. To date, however, the efficacy of these agents has fallen short of expectation, with at least
one possible explanation being the presence of feedback loops and cross-talk that exists within and between PI3K and other signaling
pathways. Accordingly, enthusiasm is again high as strategies employing therapeutic combinations are gaining pace, with encouraging
results documented in both preclinical studies and emerging clinical trials. Here, we review the agents that have reached evaluation in
early phase clinical studies of human subjects with cancer, and discuss the rationale for and use of novel drug combinations.
