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Simple Summary: The frequent activation of the PI3K/AKT/mTOR (PAM) pathway makes it an attractive therapeutic target in gynecological cancers. Many PAM inhibitors selectively target single PAM pathway nodes, which can lead to reduced efficacy and increased drug resistance. In addition, compensatory pathways can be activated when only the PAM pathway is inhibited. Here, we show that gedatolisib, a PAM inhibitor targeting multiple PAM pathway nodes, exerted greater growth-inhibitory effects relative to single-node PAM inhibitors in gynecologic cancer cell models. In addition, gedatolisib combined with inhibitors of compensatory pathways involved in the estrogen response and cell cycle progression inhibited tumor growth in endometrial and ovarian cancer mouse models. Gedatolisib in combination with other therapies has previously shown promising preliminary clinical efficacy and safety in various solid tumor types. The non-clinical data presented here support the development of gedatolisib in combination with hormonal therapy and/or cell cycle inhibitors for gynecologic cancer treatment. Background/Objectives: The PI3K/AKT/mTOR (PAM) pathway is frequently activated in gynecological cancers. Many PAM inhibitors selectively target single PAM pathway nodes, which can lead to reduced efficacy and increased drug resistance. To address these limitations, multiple PAM pathway nodes may need to be inhibited. Gedatolisib, a well-tolerated panPI3K/mTOR inhibitor targeting all Class I PI3K isoforms, mTORC1 and mTORC2, could represent an effective treatment option for patients with gynecologic cancers. Methods: Gedatolisib and other PAM inhibitors (e.g., alpelisib, capivasertib, and everolimus) were tested in endometrial, ovarian, and cervical cancer cell lines by using cell viability, cell proliferation, and flow cytometry assays. Xenograft studies evaluated gedatolisib in combination with a CDK4/6 inhibitor (palbociclib) or an anti-estrogen (fulvestrant). A pseudo-temporal transcriptomic trajectory of endometrial cancer clinical progression was computationally modeled employing data from 554 patients to correlate non-clinical studies with a potential patient group. Results: Gedatolisib induced a substantial decrease in PAM pathway activity in association with the inhibition of cell cycle progression and the decreased cell viability in vitro. Compared to single-node PAM inhibitors, gedatolisib exhibited greater growth-inhibitory effects in almost all cell lines, regardless of the PAM pathway mutations. Gedatolisib combined with either fulvestrant or palbociclib inhibited tumor growth in endometrial and ovarian cancer xenograft models. Conclusions: Gedatolisib in combination with other therapies has shown an acceptable safety profile and promising preliminary efficacy in clinical studies with various solid tumor types. The non-clinical data presented here support the development of gedatolisib combined with CDK4/6 inhibitors and/or hormonal therapy for gynecologic cancer treatment. [ABSTRACT FROM AUTHOR]

Metastatic castration‐resistant prostate cancer (mCRPC) is characterized by loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K/AKT/mTOR (PAM) pathway. Loss of the PI3K regulator PTEN is frequent during prostate cancer (PC) initiation, progression, and therapeutic resistance. Co‐targeting the PAM/AR pathways is a promising mCRPC treatment strategy but is hampered by reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors selectively spare (or weakly inhibit) one or more key nodes of the PAM pathway, potentiating drug resistance depending on the PAM pathway mutation status of patients. We posited that gedatolisib, a uniformly potent inhibitor of all class I PI3K isoforms, as well as mTORC1 and mTORC2, would be more effective than inhibitors targeting single PAM pathway nodes in PC cells. Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi‐node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single‐node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib induced anti‐proliferative and cytotoxic effects with greater potency and efficacy relative to the other PAM inhibitors, independent of PTEN/PIK3CA status. The superior effects of gedatolisib were likely associated with more effective inhibition of critical PAM‐controlled cell functions, including cell cycle, survival, protein synthesis, oxygen consumption rate, and glycolysis. Our results indicate that potent and simultaneous blockade of all class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN‐dependent resistance. Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2− advanced breast cancer. [ABSTRACT FROM AUTHOR]