KRAS-Mutant Lung Cancer: Targeting Molecular and Immunologic Pathways, Therapeutic Advantages and Restrictions
Nastaran Karimi1, Seyed Javad Moghaddam2,3
1Faculty of Medicine, Marmara University, Istanbul 34899, Turkey.
Abstract:
RAS mutations are among the most common oncogenic mutations in human cancers. Among RAS mutations, KRAS has the highest frequency and is present in almost 30% of non-small-cell lung cancer (NSCLC) patients. Lung cancer is the number one cause of mortality among cancers as a consequence of outrageous aggressiveness and late diagnosis. High mortality rates have been the reason behind numerous investigations and clinical trials to discover proper therapeutic agents targeting KRAS. These approaches include the following: direct KRAS targeting; synthetic lethality partner inhibitors; targeting of KRAS membrane association and associated metabolic rewiring; autophagy inhibitors; downstream inhibitors; and immunotherapies and other immune-modalities such as modulating inflammatory signaling transcription factors (e.g., STAT3). The majority of these have unfortunately encountered limited therapeutic outcomes due to multiple restrictive mechanisms including the presence of co-mutations. In this review we plan to summarize the past and most recent therapies under investigation, along with their therapeutic success rate and potential restrictions. This will provide useful information to improve the design of novel agents for treatment of this deadly disease.
Insights
KRAS mutations drive many cancers, especially non-small cell lung cancer (NSCLC). Current therapies targeting KRAS show limited success due to resistance mechanisms, necessitating novel treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- RAS mutations are frequent oncogenic drivers in human cancers.
- KRAS mutations are particularly prevalent in non-small cell lung cancer (NSCLC), a leading cause of cancer mortality.
- The aggressiveness and late diagnosis of lung cancer underscore the urgent need for effective KRAS-targeted therapies.
Purpose of the Study:
- To review existing and emerging therapeutic strategies targeting KRAS mutations in cancer.
- To analyze the success rates and limitations of current and investigational KRAS-targeted treatments.
- To inform the development of improved therapeutic agents for KRAS-driven malignancies.
Main Methods:
- Comprehensive literature review of preclinical and clinical studies on KRAS-targeted therapies.
- Analysis of various therapeutic approaches including direct targeting, synthetic lethality, metabolic targeting, and immunotherapies.
- Evaluation of treatment outcomes and identification of resistance mechanisms, including co-mutations.
Main Results:
- Multiple therapeutic strategies targeting KRAS are under investigation, including direct inhibition, synthetic lethality approaches, and modulation of downstream pathways.
- Many investigational therapies have shown limited clinical efficacy due to intrinsic resistance mechanisms and the presence of co-occurring mutations.
- Immunotherapies and immune-modulating agents represent a promising avenue, though challenges remain.
Conclusions:
- Targeting KRAS remains a significant challenge in oncology due to complex resistance mechanisms.
- A deeper understanding of co-mutations and tumor heterogeneity is crucial for overcoming therapeutic limitations.
- Future research should focus on combination therapies and novel strategies to improve outcomes for patients with KRAS-mutated cancers.
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