Abstract 3052: MGMT inhibition is associated with MAPK pathway inhibition and enhances Raf, MEK, ERK inhibitors and restores meaningful Temozolomide activity in melanoma

Braf and MEK inhibition leads to limited survival gains in melanoma. In this research we show that, in vitro, MGMT controls all MAPK pathway effectors. We show that triple lock - upstream and downstream, along the MAPK pathway - effectively restores durable Braf and MEK inhibitor activity and significantly sensitizes melanoma to Temozolomide. The advantage of a multiple lock approach on the MAPK pathway is substantiated by the lack of signaling cross talk. We briefly discuss how this simple MGMT based regulatory paradigm could be immediately exploited in the care of melanoma patients. We also show how this strategy was exploited in two, surviving, metastatic (to include CNS disease) melanoma patients who had failed Braf and MEK inhibition (2 and 5 years ago) who now show stable or negligible residual disease burden while continuing on an intermittent, low treatment density, combination regimen Citation Format: George C. Bobustuc, Amin B. Kassam, Dmitry Bosenko, Deborah L. Donohoe, Richard A. Rovin, Santhi D. Konduri. MGMT inhibition is associated with MAPK pathway inhibition and enhances Raf, MEK, ERK inhibitors and restores meaningful Temozolomide activity in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3052.