Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors
Honglin Jiang1,2, Ryan K Muir3, Ryan L Gonciarz3
1Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA.
Abstract:
KRAS mutations drive a quarter of cancer mortality, and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell. We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation. We converted an FDA-approved MEK inhibitor into a ferrous iron-activatable drug conjugate (FeADC) and achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor-bearing animals, with tumor-selective drug activation, producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation, and FeADCs hold promise for improving the treatment of KRAS-driven solid tumors.
Insights
New cancer drugs target ferrous iron (Fe2+) accumulation in KRAS-mutant tumors. This approach activates MEK inhibitors selectively in cancer cells, improving tolerability and treatment effectiveness for difficult-to-treat solid tumors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- KRAS mutations are a key driver of cancer mortality, with most KRAS-driven cancers currently lacking effective targeted therapies.
- Existing MAPK pathway inhibitors show limited efficacy and poor tolerability due to the high doses required for tumor cell signaling blockade.
- Oncogenic KRAS signaling is associated with increased intracellular ferrous iron (Fe2+) levels during tumor transformation.
Purpose of the Study:
- To investigate ferrous iron (Fe2+) accumulation as a targetable vulnerability in KRAS-mutant cancers.
- To develop a novel drug delivery system for enhanced MAPK pathway inhibition in KRAS-driven tumors.
- To evaluate the efficacy and tolerability of a ferrous iron-activatable drug conjugate (FeADC) in preclinical cancer models.
Main Methods:
- Engineered an FDA-approved MEK inhibitor into a ferrous iron-activatable drug conjugate (FeADC).
- Assessed FeADC activation and MAPK signaling blockade in KRAS-mutant cancer cells with varying Fe2+ levels.
- Evaluated the anti-tumor efficacy and systemic tolerability of FeADC in tumor-bearing animal models.
Main Results:
- Oncogenic KRAS signaling was confirmed to induce early and sustained ferrous iron (Fe2+) accumulation.
- The developed FeADC demonstrated potent and tumor-selective MAPK pathway blockade.
- FeADC treatment resulted in effective tumor growth inhibition and superior systemic tolerability compared to conventional MEK inhibitors in preclinical models.
Conclusions:
- Ferrous iron (Fe2+) accumulation is a unique and exploitable characteristic of KRAS-driven transformation.
- Ferrous iron-activatable drug conjugates (FeADCs) represent a promising therapeutic strategy for KRAS-mutant solid tumors.
- This approach offers a pathway to overcome the limitations of current MAPK inhibitors, improving treatment outcomes and tolerability.
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