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Targeting KRAS Mutant Non-Small-Cell Lung Cancer: Past, Present and Future
Iris Z Uras1, Herwig P Moll2, Emilio Casanova2,3
1Department of Pharmacology, Center of Physiology and Pharmacology & Comprehensive Cancer Center (CCC), Medical University of Vienna, 1090 Vienna, Austria.
Abstract:
Lung cancer is the most frequent cancer with an aggressive clinical course and high mortality rates. Most cases are diagnosed at advanced stages when treatment options are limited and the efficacy of chemotherapy is poor. The disease has a complex and heterogeneous background with non-small-cell lung cancer (NSCLC) accounting for 85% of patients and lung adenocarcinoma being the most common histological subtype. Almost 30% of adenocarcinomas of the lung are driven by an activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. The ability to inhibit the oncogenic KRAS has been the holy grail of cancer research and the search for inhibitors is immensely ongoing as KRAS-mutated tumors are among the most aggressive and refractory to treatment. Therapeutic strategies tailored for KRAS+ NSCLC rely on the blockage of KRAS functional output, cellular dependencies, metabolic features, KRAS membrane associations, direct targeting of KRAS and immunotherapy. In this review, we provide an update on the most recent advances in anti-KRAS therapy for lung tumors with mechanistic insights into biological diversity and potential clinical implications.
Insights
Targeting Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in non-small cell lung cancer (NSCLC) is crucial. This review updates advances in anti-KRAS therapies for aggressive lung tumors.
Area of Science:
- Oncology
- Molecular Biology
- Translational Medicine
Background:
- Lung cancer, particularly non-small cell lung cancer (NSCLC), has high mortality and is often diagnosed at advanced stages with poor treatment outcomes.
- KRAS mutations are prevalent in lung adenocarcinomas, driving aggressive and treatment-refractory tumors.
- Targeting oncogenic KRAS has been a significant challenge in cancer research.
Purpose of the Study:
- To provide an updated review of recent advances in anti-KRAS therapies for lung tumors.
- To offer mechanistic insights into the biological diversity of KRAS-mutated lung cancer.
- To discuss potential clinical implications of novel anti-KRAS therapeutic strategies.
Main Methods:
- Literature review of recent scientific publications on KRAS mutations and targeted therapies in lung cancer.
- Analysis of mechanistic insights into KRAS functional output, cellular dependencies, and metabolic features.
- Evaluation of therapeutic strategies including direct KRAS targeting, immunotherapy, and combination approaches.
Main Results:
- Significant progress has been made in developing inhibitors targeting KRAS mutations.
- Diverse therapeutic strategies are being explored, including blocking KRAS output, targeting KRAS-associated dependencies, and direct KRAS inhibition.
- Understanding KRAS biological diversity is key to developing effective treatments.
Conclusions:
- Targeting KRAS represents a promising frontier in the treatment of NSCLC.
- Ongoing research into anti-KRAS therapies holds potential for improving outcomes in patients with KRAS-mutated lung cancer.
- Further investigation into mechanistic insights and clinical implications is essential for advancing patient care.
