KRAS-Mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges
<p>GEFs are required to convert the GDP-bound inactive RAS to the GTP-bound active form. The RAS intrinsic hydrolytic activity allows the conversion back to the GDP inactive form. Missense mutations (such as cysteine 12 mutations) lock <span class="html-italic">KRAS</span> in the active state and disable <span class="html-italic">KRAS’s</span> function to hydrolyze GTP. KRAS G12C inhibitors can covalently bind to the switch II pocket of KRAS G12C, converting KRAS into an inactive state.</p> "> Figure 2
<p>Mechanisms of resistance to direct KRAS G12C inhibitors.</p> ">
Abstract
:1. Introduction
2. Molecular Biological Functions of KRAS
3. RAS-Mutant Biological Heterogeneity
4. Why Has Targeting KRAS Been Difficult?
5. How to Target KRAS-Mutated Lung Cancer
5.1. Indirect KRAS Inhibition
5.1.1. Targeting KRAS Membrane Associations
Target | Therapeutic Drug | Trial | Patients (n) | Overall Response Rate | Ref. |
---|---|---|---|---|---|
Farnesyltransferase inhibition | Lonafarnib + paclitaxel | Phase II | 33 | 10% | [26] |
Tipifarnib | Phase II | 44 | 0% | [27] | |
RAS farnesyl cysteine mimetic drug | Salirasib | Phase II | 33 | 0% | [30] |
Cancer vaccine | mRNA-5671 + pembrolizumab | Phase I | – | – | NCT03948763 |
5.1.2. Targeting KRAS-Regulated Pathways
Target | Therapeutic Drug | Trial | Patients (n) | Overall Response Rate | Ref. |
---|---|---|---|---|---|
Fatty acid synthase | TVB-2640 | Phase I | 31 | 0 | [33] |
RAF/MEK/ERK pathway inhibition | Selumetinib + docetaxel | Phase III | 510 | 20% | [36] |
Trametinib | Phase II | 129 | 12% | [38] | |
Sorafenib | Phase III | 703 | 2.9% | [40] | |
PI3K/AKT/mTOR pathway inhibition | Buparlisib | Phase II | 63 | 3% | [42] |
Ridaforolimus | Phase II | 79 | 1% | [41] |
6. Immunotherapy in KRAS-Mutant NSCLC
7. CDK4/6 and SHP2 Inhibition
8. Direct KRAS G12C Inhibition
9. Resistance to KRAS G12C Inhibitor
10. Open Questions and Future Challenges
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Target | Therapeutic Drug | Trial | Patients (n) | Overall Response Rate | Ref. |
---|---|---|---|---|---|
Immune checkpoint inhibition | Nivolumab | EAP | 324 | 20% | [60] |
CDK inhibition | Abemaciclib vs. erlotinib | Phase III | 270 | 9% | [59] |
Palbociclib | Phase II | 53 | 6% | [61] | |
SHP2 inhibition | RMC 4630 | Phase I | 18 | 11% | [62] |
Target | Therapeutic Drug | Trial | Patients (n) | Overall Response Rate | Ref. |
---|---|---|---|---|---|
Protein-based inhibition (KRAS binders) | AMG 510/sotorasib | Phase I–III | 129 | 32.2% | NCT03600883 CodeBreak 100 |
MRTX 849/adragasib | Phase I–III | 79 | 45% | NCT03785249 KRYSTAL-1 trial | |
JNJ-74699157 | Phase I | 140 | NCT04006301 | ||
GDC-6036 | Phase I | NCT04449874 | |||
D-1553 | Phase I | NCT04585035 |
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Ceddia, S.; Landi, L.; Cappuzzo, F. KRAS-Mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges. Int. J. Mol. Sci. 2022, 23, 9391. https://doi.org/10.3390/ijms23169391
Ceddia S, Landi L, Cappuzzo F. KRAS-Mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges. International Journal of Molecular Sciences. 2022; 23(16):9391. https://doi.org/10.3390/ijms23169391
Chicago/Turabian StyleCeddia, Serena, Lorenza Landi, and Federico Cappuzzo. 2022. "KRAS-Mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges" International Journal of Molecular Sciences 23, no. 16: 9391. https://doi.org/10.3390/ijms23169391