Combination of MDM2 inhibition with milademetan and MEK inhibition leads to improved anti-tumor activity in cancer models harboring WT TP53

Background: Loss of p53 activity is important for tumor initiation and progression. While approximately 50% tumors lose through inactivating mutations in TP53, harness other mechanisms to inactivate p53, including MDM2, an E3 ligase that targets proteasomal degradation. Milademetan MDM2 inhibitor currently being evaluated clinical trials. The MAPK pathway commonly activated by the RTK-RAS-RAF-MAPK axis or sustain proliferative signaling, growth, survival. Here we whether inhibition using MEK1/2 trametinib could further enhance milademetan antitumor activity. Materials Methods: We multiple cancer models derived from different types (including lung cancer, renal cell carcinoma, melanoma, colorectal cancers sarcomas) based on three genetic categories represent varying levels potential dependence: gene amplification (and WT TP53), CDKN2A homozygous loss TP53 alone. effects milademetan, combination signaling pathways, vitro proliferation synergy indices (Loewe, Bliss HSA), vivo growth. Results: induced reactivation as measured induction p21 PUMA proteins whereas inhibited activation pERK1/2 representing with amp (∼1–4% solid tumors, depending copy number cutoff), (6.2% also harbor Tirunagaru et al., ASCO 2022), only (∼40% tumors). majority tested demonstrated trametinib, known oncogenic drivers such RAS RAF activating mutations. xenograft experiments A549 (lung adenocarcinoma loss, KRAS G12S, TP53) HT1197 (urothelial carcinoma NRAS Q61R plus was superior either agent Conclusions: combinatorial superiority vivo. These data support exploration patients whose selected alterations, amplification, TP53. Conflict interest: Ownership: Authors are employees shareholders Rain Therapeutics.