The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling

Abstract

Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance. Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT). However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined. In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

“…Oncogenic PI3K signaling frequently occurs in prostate cancer, and is invariably activated in metastatic disease [ 21 , 143 , 144 , 145 ]. The PI3Ks are a family of intracellular signal transduction enzymes that can be separated into 3 structurally and functionally defined classes (Class I, that is subdivided into Class 1A and Class 1B, Class II and Class III).…”

“…The PI3Ks are a family of intracellular signal transduction enzymes that can be separated into 3 structurally and functionally defined classes (Class I, that is subdivided into Class 1A and Class 1B, Class II and Class III). Here, we focus on Class1A PI3Ks, which have been shown to contribute to prostate tumor formation and progression [ 146 , 147 ] (for more information on Class II and Class III PI3Ks refer to [ 144 , 148 ]). Class IA PI3Ks function as heterodimers comprised of a catalytic isoform (p110α, p110β, and p110δ) and a regulatory subunit (p85α, p85β, p55α, p55γ or p50α) that catalyze the convsion of PIP2 to PIP3 upon recruitment to the cytoplasmic domain following the activation of upstream receptors (e.g., receptor tyrosine kinases, RTKs, G-protein coupled receptors, GPCRs) and small GTPases [ 147 ].…”

“…In prostate cancer, activation of the PI3K–AKT–mTOR cascade occurs through multiple mechanisms (reviewed in [ 144 ]). Although PTEN loss is the most frequent cause, a range of distinct genetic alterations can also cause oncogenic signaling of this pathway.…”

“…A range of highly potent PI3K catalytic isoform-specific inhibitors have also been developed, providing an opportunity to reduce the therapeutic dose administered and limit toxicity [ 154 ]. While PIK3CA mutant prostate cancers have been shown to respond to p110α isoform-specific inhibition, previous work by us and others has shown that targeting p110α alone in prostate cancers with PTEN loss is not efficacious, owing to p110β dependency [ 21 , 144 , 168 , 169 ]. Although acquisition of PTEN genetic alterations in response to the p110α inhibitor alpelisib (BYL719) have been shown to drive resistance in metastatic breast cancer patients [ 85 ], indicating that similar mechanisms of resistance may emerge in PTEN-deficient prostate cancer, p110α inhibition may still prove to be efficacious against prostate cancers that are both PTEN-deficient and carrying an activating PIK3CA mutation.…”

“…AKT is a serine/threonine protein kinase, of which three structurally similar isoforms exist (AKT1, AKT2 and AKT3) that are differentially expressed across tissue compartments, with AKT1 being the most abundantly expressed across most tissues [ 192 ]. Activating mutations in AKT1–3 are relatively rare in prostate cancer, while gene amplification has been observed in up to 4.5% ( AKT1 ), 2% ( AKT2 ), and 4.7% ( AKT3 ) of prostate cancer cases, respectively [ 144 ]. The importance of each AKT isoform in PTEN-deficient prostate cancer remains unclear, with some preclinical data suggesting a higher dependency on AKT2 compared to AKT1 [ 193 ], yet only deletion of Akt1 and not Akt2 has been shown to suppress prostate neoplasia in a Pten +/− transgenic mouse [ 194 , 195 ].…”