Synergy was apparent at various concentration combinations of SNS-510 with CDK4/6i ribociclib and palbociclib in the ER+ breast cancer cell lines MCF7 (CDKN2b del, PI3Kca mut) and EFM19 (CDKN2A del, PI3Kca mut), with the BCL2i venetoclax in both the anaplastic large cell lymphoma SR (CDKN2a del) and the DLBCL-GCB SU-DHL-4 (TP53 mut) cell lines, and with the K-Ras G12Ci AMG-510 in the K-Ras mutated Calu-1 (lung) and Mia-PaCA-2 (pancreas) cell lines. The observed synergies support a potential role of PDK1 inhibition to reverse resistance and/or improve activity of CDK4/6i in breast cancer, BCL2i in lymphoma and K-Rasi in G12C mutated cancers.