Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors

Abstract

The phosphoinositide 3-kinase (PI3K) pathway plays an integral role in many cellular processes and is frequently altered in cancer, contributing to tumor growth and survival. Small molecule inhibitors have been developed that target the three major nodes of this pathway: PI3K, AKT, and mammalian target of rapamycin. However, because oncogenic PI3K pathway activation is achieved in diverse, potentially redundant ways, the clinical efficacy of these inhibitors as monotherapies has, so far, been limited, despite demonstrating promising preclinical activity. Moreover, pathway activation is associated with resistance to other therapies; thus, in combination, PI3K pathway inhibitors could restore therapeutic sensitivity to these agents. To maximize therapeutic benefit, drug combinations and schedules must be explored to identify those with the highest efficacy and lowest toxicity overlap. In addition, defining appropriate patient subpopulations, for both monotherapy and drug combinations, will be important. However, identifying predictive biomarkers remains a challenge.

Conflict of interest statement

Author’s disclosures of potential conflicts of interest are found in the article online at www.jco.org.

Figures

Fig 1.

Common PI3K pathway aberrations found in a variety of solid tumor types. Activation of the PI3K pathway contributes to tumor growth, survival, and resistance to anticancer therapies. FGFR2, fibroblast growth factor receptor 2; GBM, glioblastoma multiforme; HER2, human epidermal growth factor receptor 2; HNSCC, head and neck squamous cell carcinoma; INPP4B, inositol polyphosphate 4-phosphatase type II; MET, hepatocyte growth factor receptor; mTORC, mammalian target of rapamycin complex; NSCLC, non–small-cell lung cancer; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog; PTPN12, protein tyrosine phosphatase nonreceptor 12; RTK, receptor tyrosine kinase; SCLC, small-cell lung cancer; TNBC, triple-negative breast cancer. Adapted from a figure provided by Ana Maria Gonzalez-Angulo.

Fig 2.

Common nodes of resistance to targeted therapies within the PI3K pathway. PI3K pathway alterations that confer resistance to targeted therapies across various tumor types are shown. CRC, colorectal cancer; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; INPP4B, inositol polyphosphate 4-phosphatase type II; MET, hepatocyte growth factor receptor; mTORC, mammalian target of rapamycin complex; PDK1, phosphoinositide-dependent kinase 1; PI3K, phosphoinositide 3-kinase; PIK3CA, phosphatidylinositol 3-kinase catalytic subunit alpha; PIK3CG, phosphatidylinositol 3-kinase catalytic subunit gamma; PIK3R2, phosphatidylinositol 3-kinase regulatory subunit beta; PIP2, phosphatidylinositol 4,5- bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase.

Fig 3.

Targeting the PI3K pathway in cancer with small-molecule inhibitors. Inhibitors discussed in the text are included in the figure. IGF-1R, insulin-like growth factor 1 receptor; InsR, insulin receptor; IRS1, insulin receptor substrate 1; mTORC, mammalian target of rapamycin complex; PDK1, phosphoinositide-dependent kinase 1; PI3K, phosphoinositide 3-kinase; RTK, receptor tyrosine kinase.