Although there is a significant scientific rationale for targeting the PI3K pathway in breast cancer, research findings presented recently at the 2014 San Antonio Breast Cancer Symposium (SABCS) highlight the inherent complexities in using agents directed at this cell-signaling network. Given the extensive heterogeneity of breast cancer, the identification of patients most likely to respond to these drugs is becoming increasingly pressing and challenging.
These challenges were illustrated at SABCS in data from the phase II FERGI study, which evaluated the pan- PI3K inhibitor pictilisib (GDC-0941) in combination with fulvestrant in patients with metastatic breast cancer. The addition of pictilisib demonstrat- ed statistically significant progression-free survival (PFS) benefits only in the subset of patients with both estrogen receptor (ER)– and progester- one receptor (PR)–positive disease. Thus far, the most successful strategies in attacking the PI3K pathway have been aimed at the downstream mammalian target of rapamycin (mTOR). Yet, while mTOR inhibitors remain the only class of PI3K path- way-targeting agent to have attained regulatory approval, a number of drugs targeting PI3K and dual inhibitors of PI3K/mTOR are now in the late stages of clinical development in patients with breast cancer (Table 1).PI3K Conducts Cell-Signaling Symphony
The phosphatidylinositol-3 kinase pathway is the most highly dysregulated signaling network in breast cancer. It has also been implicated in development of resistance to other kinds of breast cancer therapy, most significantly endocrine therapy, human epidermal growth factor receptor 2 (HER2)–directed therapy, and chemotherapy, suggesting that agents directed at PI3K may be promising in counteracting drug resistance that limits current treatments. Mutations in the genes encoding the PI3K pathway are particularly common, making this an extremely attractive point for therapeutic intervention.
PI3Ks encompass a family of kinases that phosphorylate phosphoinositide lipids. Three classes and numerous subclasses have been identified, but the most relevant from an oncology perspective are class IA PI3Ks. Their kinase activity is switched on by receptor tyrosine kinases (RTKs) and, upon activation, they phosphorylate their phosphoinositide target, phosphatidylinositol-4,5-bisphosphate (PIP2), to form phosphatidylinositol-3,4,5-triphosphate (PIP3).
From its position in the cell membrane, PIP3 is able to recruit and activate an array of kinases to propagate a plethora of different cell-signaling pathways downstream of RT
Ks. One of the best characterized is Akt, which in turn regulates the function of a broad range of proteins involved in integral cellular processes. A key downstream effector of Akt is mTOR, which is a master regulator of cell growth and metabolism. So important are these two proteins that the network is often referred to as the PI3K/Akt/mTOR pathway.Methods of Attacking Pathway
Cell survival, growth, proliferation, metabolism, motility, and adhesion are a small representation of the cellular functions controlled by PI3K and its downstream elements. PI3K and the phosphatase that opposes its action, phosphatase and tensin homolog (PTEN), are conductors of a cell-signaling symphony.
In breast cancer, aberrant activation of at least one component of this pathway can be observed in more than 70% of cases. Mutations in the genes that encode PI3K itself are common, observed in around 18% of patients. PI3K is a heterodimeric protein composed of a catalytic (p110) subunit and a regulatory (p50/p55/p85) subunit. Three isoforms of the catalytic subunit exist (a, β, and δ), which are encoded by three genes: PIK3CA, PIK3CB, and PIK3CD, respectively. The PIK3CA gene is particularly frequently altered in breast cancer (20%-25%). Mutations occur most often in the parts of the gene that encode the helical and kinase domains of the PI3K protein, and three “hotspots” have been identified—E542K, E545K, and H1047R—all of which produce a constitutively active kinase that drives oncogenesis.