Molecular Pathways: PI3K Pathway Phosphatases as Biomarkers for Cancer Prognosis and Therapy

Abstract

Cancer research has seen tremendous changes over the past decade. Fast progress in sequencing technology has afforded us with landmark genetic alterations, which had immediate impact on clinical science and practice by pointing to new kinase targets, such as PI 3-Kinase, the EGF receptor or BRAF. The PI 3-Kinase pathway for growth control has emerged as a prime example for both oncogene activation and tumor suppressor loss in cancer. Here, we discuss how therapy using PI 3-kinase pathway inhibitors could benefit from information on specific phosphatases, which naturally antagonize the kinase targets. This PI 3-Kinase pathway is found mutated in most cancer types, including prostate, breast, colon and brain tumors. The tumor suppressing phosphatases operate at two levels. Lipid level phosphatases, such as PTEN and INPP4b revert PI 3-kinase activity to keep the lipid second messengers inactive. At the protein level, PHLPP1/2 protein phosphatases inactivate AKT kinase, thus antagonizing mTOR complex 2 activity. However, in contrast to their kinase counterparts the phosphatases are unlikely drug targets. They would need to be stimulated by therapy and are commonly deleted and mutated in cancer. Yet, since they occupy critical nodes in preventing cancer initiation and progression, the information on their status has tremendous potential in outcome prediction, and in matching the available kinase inhibitor repertoire with the right patients.

PTEN Functions by Recruitment to Cytoplasmic Vesicles

“…Downstream of these kinases, lipid phosphatases are critical to PI(3)P homeostasis. The INPP4b phosphatase, which produces PI(3)P from PI(3,4)P 2 , has been identified as a tumor suppressor (Chen et al, 2014; Fedele et al, 2010; Gewinner et al, 2009), consistent with a role in supporting PTEN via PI(3)P production. Finally, the Myotubularin phosphatase, which dephosphorylates PI(3)P (Taylor et al, 2000), is essential for cell survival through AKT signaling (Razidlo et al, 2011), consistent with suppression of the PI(3)P/PTEN axis.…”

Improved survival of patients with melanoma brain metastases in the era of targeted BRAF and immune checkpoint therapies

“…29,30 In a similar fashion, the CNS has been described as an immune privileged site in which direct stimulation or recruitment of cytotoxic T-cell populations may be less robust compared with extracranial tumor sites treated with immunotherapy. 7,32 Encouragingly, the median OS of patients with MBM in the current data set appears much improved compared with historical data. 7,32 Encouragingly, the median OS of patients with MBM in the current data set appears much improved compared with historical data.…”

“…31 Another possibility is that neither class of therapies directly target the biology underlying brain tropism for some melanoma tumors. 7,32 Encouragingly, the median OS of patients with MBM in the current data set appears much improved compared with historical data. Davies et al reported a median OS of 4.7 months after a diagnosis of MBM in patients who developed MBM during clinical trial participation between 1986 and 2004.…”

MYC Drives Pten/Trp53-Deficient Proliferation and Metastasis due to IL6 Secretion and AKT Suppression via PHLPP2

“…We showed previously that the Akt phosphatase Phlpp2 (35, 36), but not the Phlpp1 homolog, is specifically induced by Akt pathway activation to limit the signaling output ((15), and reviewed in (37)). As shown in Fig.…”