There is an unmet need in prostate cancer for effective therapies to prevent the emergence of resistance. Combinations of small molecules targeting key pathways are a promising strategy. I investigated how populations of the early metastatic prostate cancer cell line LNCaP respond at the proteomic and pheno-typic levels to six clinically-relevant, one-drug treatments and their 15 pairs of two-drug combinations, administered simultaneously to treatment-naive cells. After 24 hours of drug addition for all 21 drug treatments I measured 52 total- proteins by selected-reaction monitoring mass-spectrometry based proteomics (SRM), 20 phospho-proteins, and 50 total-proteins by reverse-phase protein ar- rays (RPPA). I measured phenotypic effects on cell proliferation and apoptosis in all conditions using phase-contrast and fluorescence microscopy. Network analysis identified (phospho)-proteins with large responses to drug treatments that are druggable with FDA-approved drugs or have nearest-neighbors that are druggable. A total of ten drugs targeting these nearest responder (phospho)-proteins were tested in single, double, and triple combinations. I found that 7 out of 10 triple combinations co-targeting androgen receptor and PI3K pathways were no more effective than the two-drug combination at the doses tested: PRKC (en- zastaurin), MAPK (losmapimod), STAT3 (napabucasin), HDAC (panobinostat), SRC (saracatinib), casein kinase (silmitasertib), MAPK (ulixertinib). I was un- able to determine the relative efficacy of aurora kinase B (barasertib), 14-3-3 in- hibor (BV02) and their combinations. For one drug tested (dinaciclib, CDK1/2 inhibitor) I found increased efficacy with PI3K signaling inhibition (MK2206, AKT1/2 inhibitor). I propose a simple model where blocking PI3K signaling in LNCaP cells causes a partial inhibition of the cell cycle G1/S transition through hypo- phosphorylation of RB and hypo-phosphorylation of CDK2 at the G2/M transi- tion. These effects can be enhanced by co-targeting PI3K signaling and drivers of the cell cycle using the CDK1/2 inhibitor dinaciclib. I also investigated how proteins that interact with the androgen receptor change in response to perturbation in a prostate cancer context (VCaP cell line). I identified 111 proteins with affinity purification mass spectrometry (AP-MS). These proteins have diverse functions and many have not been reported in the literature. I found that treatment with an antagonist (enzalutamide) has mini- mal effects on the interactors. Interactors such as metadherin (MDTH) and chromosome transmission fidelity factor 8 (CHTF8) are recurrently altered in patient cohorts. Metadherin is recurrently amplified and may represent a promising drug target.