We investigated the growth-inhibitory activity of the pan-AKT inhibitor ipatasertib in combination with other targeted therapies. Thirty-nine patient-derived cancer cell lines from the NCI Patient-Derived Models Repository and nine NCI-60 tumor cell lines were grown as mct-spheroids. The mct-spheroids, a mixture of tumor cells (60%), endothelial cells (25%), and mesenchymal stem cells (15%), were established for 3 days before compounds(s) were added. All agents were tested at concentrations up to the reported clinical C values or a high concentration of 10 μM. Cell viability was assayed using CellTiter-Glo 3D after 7 days of exposure. Ipatasertib was selective for tumor cells harboring activating PI3K/AKT/mTOR pathway mutations. Dual inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways was very effective. The combination of ipatasertib with the MEK inhibitor selumetinib or the ERK inhibitor ravoxertinib resulted in additive and/or greater-than-additive cytotoxicity in approximately half the cell lines screened. The V600E mutation-specific BRAF inhibitor vemurafenib and the KRAS G12C selective inhibitor sotorasib in combination with ipatasertib were active in the eight BRAF V600E and four KRAS G12C mutant-containing cell lines, respectively. Vertical inhibition of the PI3K/AKT/mTOR pathway with the mTORC1/2 kinase inhibitor sapanisertib demonstrated additive and/or greater-than-additive effects in multiple cell lines. In early experiments, there was a correlation between the response to ipatasertib and selumetinib in two patient-derived tumor lines grown as mct-spheroids and the corresponding patient-derived xenografts. All data are accessible via the PubChem BioAssay public database.