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Cytotoxic activity of KRAS inhibitors in combination with chemotherapeutics
Gerhard Hamilton1, Adelina Plangger1
1Department Of Vascular Surgery, Medical University Of Vienna, Vienna, Austria.
Introduction:
KRAS is the most frequently mutated oncogenic driver in pancreatic, lung, and colon cancer. Recently, KRAS inhibitors in clinical use show promising activity but most responses are partial and drug resistance develops. The use of therapeutics in combination with KRAS inhibitors are expected to improve outcomes.
Areas Covered:
This review describes the KRAS G12C mutation-specific inhibitors and the SOS1-targeting inhibitors that reduce the GTP-loading of wildtype and mutated KRAS. Both types of compounds reduce tumor cell proliferation in vitro and in vivo. The combinations of the various KRAS inhibitors with downstream signaling effectors, modulators of KRAS-associated metabolic alterations and chemotherapeutics are summarized.
Expert Opinion:
The clinical potency of mutated KRAS-specific inhibitors needs to be improved by suitable drug combinations. Inhibition of downstream signaling cascades increases toxicity and other combinations exploited comprise G12C-directed inhibitors with SOS1 inhibitors, glucose/glutamine metabolic modulators, classical chemotherapeutics, and others. The most suitable inhibitor combinations corroborated in preclinical development await clinical verification.
Insights
KRAS inhibitors show promise for cancer treatment but require combination therapies to improve efficacy and overcome resistance. Further research into combining KRAS inhibitors with other agents is crucial for better patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- KRAS mutations are key drivers in pancreatic, lung, and colon cancers.
- Current KRAS inhibitors offer partial responses and face drug resistance.
- Combination therapies are essential for improving KRAS inhibitor effectiveness.
Purpose of the Study:
- To review KRAS G12C-specific and SOS1-targeting inhibitors.
- To summarize combinations of KRAS inhibitors with other therapeutic agents.
- To discuss the potential of combination therapies for overcoming resistance and improving outcomes.
Main Methods:
- Review of KRAS G12C and SOS1 inhibitor mechanisms.
- Summary of preclinical data on various combination strategies.
- Analysis of combinations with downstream effectors, metabolic modulators, and chemotherapeutics.
Main Results:
- KRAS G12C and SOS1 inhibitors reduce tumor cell proliferation in vitro and in vivo.
- Combinations explored include KRAS inhibitors with downstream signaling modulators, metabolic regulators, and chemotherapeutics.
- Preclinical data supports the potential of these combinations.
Conclusions:
- Improved clinical potency of KRAS inhibitors necessitates effective drug combinations.
- Combination strategies aim to enhance efficacy and mitigate resistance.
- Further clinical validation is required for promising preclinical combinations.
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