Eric Collisson, MD, Professor of Medicine at UC San Francisco, and Adam Renslo, Ph.D., Professor, Pharmaceutical Chemistry at UC San Francisco. In this video, they speak about Ferrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors.
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Overview:
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KRAS mutations are responsible for one-quarter of cancer deaths, and the majority are untreatable. Several MAPK pathway inhibitors are FDA-approved, however, they are poorly tolerated at the levels required to effectively suppress RAS/RAF/MAPK signaling in tumor cells. Oncogenic KRAS signaling increased ferrous iron (Fe2+) buildup early in and during mutant KRAS-mediated transformation, we discovered. We were able to establish potent MAPK inhibition in tumor cells while sparing normal tissues by converting an FDA-approved MEK inhibitor into a ferrous iron-activatable drug combination (FeADC). This breakthrough enabled the long-term, effective treatment of tumor-bearing mice using tumor-selective drug activation, resulting in greater systemic tolerability. The ferrous iron buildup is a characteristic of KRAS transformation that can be exploited, and FeADCs has the potential for enhancing the treatment of KRAS-driven solid malignancies.