Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment

Abstract

The reduction in androgen synthesis and the blockade of the androgen receptor (AR) function by chemical castration and AR signaling inhibitors represent the main treatment lines for the initial stages of prostate cancer. Unfortunately, resistance mechanisms ultimately develop due to alterations in the AR pathway, such as gene amplification or mutations, and also the emergence of alternative pathways that render the tumor less or, more rarely, completely independent of androgen activation. An essential oncogenic axis activated in prostate cancer is the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, as evidenced by the frequent alterations of the negative regulator phosphatase and tensin homolog (PTEN) and by the activating mutations in PI3K subunits. Additionally, crosstalk and reciprocal feedback loops between androgen signaling and the PI3K/AKT/mTOR signaling cascade that activate pro-survival signals and play an essential role in disease recurrence and progression have been evidenced. Inhibitors addressing different players of the PI3K/AKT/mTOR pathway have been evaluated in the clinic. Only a limited benefit has been reported in prostate cancer up to now due to the associated side effects, so novel combination approaches and biomarkers predictive of patient response are urgently needed. Here, we reviewed recent data on the crosstalk between AR signaling and the PI3K/AKT/mTOR pathway, the selective inhibitors identified, and the most advanced clinical studies, with a focus on combination treatments. A deeper understanding of the complex molecular mechanisms involved in disease progression and treatment resistance is essential to further guide therapeutic approaches with improved outcomes.

Keywords: AKT; PI3K; androgen receptor; mTOR; prostate cancer.

Figure 1

Schematic overview of the AR and PI3K/AKT/mTOR signaling pathways and their crosstalk. Selected approved and advanced inhibitors addressing these pathways are indicated.

Figure 2

AR inhibitors launched or in late-stage clinical trials.

Figure 3

The AR-targeted PROTAC bavdegalutamide (ARV-110).

Figure 4

The AR-V7 inhibitor EPI-506.

Figure 5

FDA-approved inhibitors of PI3K.

Figure 6

Inhibitors of PI3K in advanced clinical trials.

Figure 7

Inhibitors of AKT in advanced clinical trials.

Figure 8

Macrocyclic allosteric mTOR inhibitors.

Figure 9

Mutant-selective allosteric inhibitors of PI3Kα.

Figure 10

Compound HL-8: a recently reported PROTAC degrader of PI3K.

Figure 11

PROTAC degraders of AKT.