MDM2 Antagonists Help CDK4/6 Inhibitors Overcome Resistance in Melanoma

While cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have seen success in treating breast cancer, they have not been as successful in other tumor types, where cancer cells have developed resistance. However, pairing CDK4/6 inhibitors with a murine double minute (MDM2) antagonist can help the inhibitors overcome resistance, according to a new study in Science Translational Medicine.

Researchers found that the protein p21 was necessary for the proliferation of cells treated with CDK4/6 inhibitors, but after treatment, cells upregulated cyclin D1, which led to a shortage of p21, and thus caused tumors to be resistant to treatment with CDK4/6 inhibitors. They used melanoma patient—derived xenografts in mouse models.

The investigators used an MDM2 antagonist to stabilize p53, which helps to induce expression of p21 and counteract the resistance to CDK4/6 inhibitors.

“MDM2 inhibitors require functional p53 to work. In many types of cancer, p53 will be mutated or deleted, and this loss of tumor suppressor allows tumors to progress,” study author Anna Vilgelm, MD, PhD, research assistant professor of pharmacology at the Vanderbilt-Ingram Cancer Center, explained in a statement. “In melanoma, however, mutations of p53 are relatively rare. Therefore, the combination therapy of MDM2 and CDK4/6 inhibitors is likely to benefit a large group of melanoma patients.”

Using the combination treatment of MDM2 and CDK4/6 inhibitors, the researchers saw tumor regression in multiple mouse models and in human tumor slice culture assays. However, only patients with p53 and RB wild-type melanoma are likely to benefit from the combination therapy of MDM2 and CDK4/6 inhibitors, Vilgelm added.

This research provides another potential therapeutic option for patients with melanoma, nearly half of whom are not responsive to immunotherapies. In addition, patients who are responsive to targeted therapies often develop a resistance that requires a second-line treatment.

“I think this is a good potential second-line treatment for melanoma patients with p53 and RB wild-type tumors who don’t respond to or who develop resistance to immunotherapies or other targeted therapies,” Vilgelm said. “I think this combination really makes sense in terms of the genetics of melanoma.”

Reference

Vilgelm AE, Saleh N, Shattuck-Brandt R, et al. MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21 [published online August 14, 2019]. Sci Transl Med. doi: 10.1126/scitranslmed.aav7171.