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Published on: August 23, 2019
A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer
Abstract:
Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RAS WT cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RAS WT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases expressed in RAS WT and normal cells but repressed in RAS mutant cancer cells. ADT-007 binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 displayed unique advantages over mutant-specific KRAS and pan-KRAS inhibitors, as well as other pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms leading to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for RAS-driven cancers.
Significance:
ADT-007 has unique pharmacological properties with distinct advantages over other RAS inhibitors by circumventing resistance and activating antitumor immunity. ADT-007 prodrugs and analogs with oral bioavailability warrant further development for RAS-driven cancers.
Insights
A new drug, ADT-007, effectively inhibits RAS-driven cancers by targeting activated RAS, unlike other inhibitors. It shows promise for treating colorectal and pancreatic cancers with potential for oral administration.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RAS proteins are key regulators of cell signaling, and their mutations drive many cancers.
- Current RAS inhibitors often target specific mutations or isoforms, leading to resistance.
- A need exists for novel inhibitors that broadly target RAS-driven cancers and overcome resistance mechanisms.
Purpose of the Study:
- To introduce and characterize ADT-007, a novel pan-RAS inhibitor.
- To evaluate the efficacy and mechanism of action of ADT-007 in preclinical cancer models.
- To compare ADT-007 with existing RAS inhibitors and assess its potential for clinical development.
Main Methods:
- In vitro assays to assess ADT-007's inhibition of cancer cell growth across various RAS mutation statuses.
- Studies to elucidate the molecular mechanism of ADT-007, including its binding to RAS and downstream signaling.
- In vivo studies using mouse models of colorectal and pancreatic cancer to evaluate antitumor activity and immune modulation.
- Assessment of ADT-007 prodrugs for oral bioavailability and efficacy.
Main Results:
- ADT-007 potently inhibited growth in RAS mutant cancer cells, irrespective of mutation type or RAS isozyme.
- Sensitivity to ADT-007 required RAS activation and proliferation dependence, while normal cells and certain RAS wild-type cancers were insensitive.
- ADT-007 binds nucleotide-free RAS, blocking GTP activation, MAPK/AKT signaling, and inducing mitotic arrest and apoptosis.
- Local administration demonstrated robust antitumor activity in mouse models, associated with suppressed MAPK signaling and enhanced tumor immunity.
- Oral administration of an ADT-007 prodrug also showed significant tumor growth inhibition.
Conclusions:
- ADT-007 exhibits unique pharmacological properties, offering advantages over existing RAS inhibitors by overcoming resistance.
- ADT-007 activates innate and adaptive anti-tumor immunity within the tumor microenvironment.
- Further development of ADT-007 prodrugs and analogs with oral bioavailability is warranted for RAS-driven cancers.
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