Targeted therapy combinations with ipatasertib in multi-cell type 3D tumor spheroid models

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• The PI3K/AKT/mTOR pathway is frequently dysregulated in cancer, making it a key target for therapy.
• Ipatasertib is a pan-AKT inhibitor investigated for its anti-cancer properties.
• Combination therapies are crucial for overcoming resistance and improving treatment efficacy in cancer.

Purpose of the Study:

• To evaluate the growth-inhibitory activity of ipatasertib in combination with other targeted therapies.
• To identify specific cancer cell mutations that sensitize tumors to ipatasertib.
• To explore the efficacy of dual pathway inhibition strategies.

Main Methods:

• Utilized 39 patient-derived and 9 NCI-60 cancer cell lines grown as multicellular spheroids (mct-spheroids).
• Assessed cell viability using CellTiter-Glo 3D assay after 7-day exposure to compounds up to clinical Cmax or 10 μM.
• Tested combinations of ipatasertib with inhibitors of RAS/MEK/ERK, BRAF, and mTOR pathways.

Main Results:

• Ipatasertib demonstrated selectivity for tumor cells with activating PI3K/AKT/mTOR pathway mutations.
• Combinations of ipatasertib with MEK (selumetinib) or ERK (ravoxertinib) inhibitors showed additive or greater-than-additive cytotoxicity in about half of the cell lines.
• Specific BRAF and KRAS mutant cell lines responded to ipatasertib combined with BRAF (vemurafenib) or KRAS (sotorasib) inhibitors, respectively.
• Vertical inhibition with sapanisertib (mTORC1/2 inhibitor) also yielded additive or greater-than-additive effects.

Conclusions:

• Dual inhibition of PI3K/AKT/mTOR and RAS/MEK/ERK pathways is a promising strategy.
• Ipatasertib in combination with other targeted agents shows potential for treating specific cancer subtypes.
• Early data suggest a correlation between spheroid and xenograft responses to ipatasertib and selumetinib combinations.