TARGETING THE PI3K/AKT/MTOR PATHWAY IN PROSTATE CANCER: OVERCOMING RESISTANCE VIA COMBINATION STRATEGIES

Prostate cancer remains a leading malignancy in men worldwide, with aberrant activation of the PI3K/AKT/mTOR signaling pathway recognized as a central driver of disease progression and therapeutic resistance. Loss of PTEN and recurrent mutations in PIK3CA, AKT, and mTOR sustain oncogenic signaling, promoting castration-resistant prostate cancer (CRPC). The pathway’s reciprocal crosstalk with androgen receptor (AR), MAPK, and WNT signaling underscores its role at the crossroads of multiple oncogenic networks, complicating monotherapy approaches. A wide spectrum of inhibitors—including pan-PI3K, isoform-selective PI3K, AKT, mTOR, and dual PI3K/mTOR agents—have demonstrated biological activity, yet clinical outcomes remain modest due to compensatory signaling and toxicity. Emerging strategies emphasize rational combination therapies, particularly with AR blockade, PARP inhibitors, immune checkpoint inhibitors, and chemotherapy, to enhance efficacy and overcome resistance. Novel dual-targeted agents such as PI3K/HDAC inhibitors further highlight the potential of multipathway inhibition in biomarker-defined patient populations. Collectively, these advances position PI3K-targeted therapies as a cornerstone of next-generation prostate cancer management, offering promise for durable outcomes in CRPC.

Key words :PI3K, AKT, mTOR, PTEN, Resistance