Emerging Therapies in Kirsten Rat Sarcoma Virus (+) Non-Small-Cell Lung Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. KRAS Biology
2.1. Structure and Signaling Pathways
2.2. Cooperation of KRAS and WNT Pathways
2.3. Mutations
2.4. Comutations
2.5. Why Was the KRAS Mutation Undruggable?
3. Direct Targeting of KRAS
3.1. Sotorasib (AMG510)
3.2. Adagrasib (MRTX849)
3.3. Novel Direct Inhibitors of KRAS G12C
4. Resistance to KRAS-G12C Inhibitors
5. Indirect Inhibition of KRAS
5.1. Inhibitors of the Upstream Signaling Pathway
- EGFR inhibitors
- SHP2 and SOS1 inhibitors
5.2. Inhibitors of the Downstream Signaling Pathway
- MAPK pathway (RAF/MEK/ERK)
- PI3K/AKT/mTOR pathway
5.3. FAK Inhibitors
5.4. DDR1 Inhibitors
5.5. YB-1 Inhibitors
5.6. HSP90 Inhibitors
5.7. CDK 4/6 Inhibitors
6. Platinum-Based Chemotherapy in KRAS-Mutated NSCLC
7. Immunotherapy in KRAS-Mutated NSCLC
8. KRAS-G12V and -G12D Mutations
9. Other Emerging Therapies
10. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Trial | Phase | KRAS Inhibitor | Combinations | Status/Outcomes | References |
---|---|---|---|---|---|
CodeBreak 100 NCT03600883 | I/II | sotorasib | monotherapy | mPFS 6.8 months mOS 12.5 months FDA Approval | [52,53,56] |
CodeBreak 200 NCT04303780 | III | sotorasib | monotherapy vs. docetaxel | mPFS 5.6 months vs. 4.5 months (HR 0.66) | [57,58,59] |
CodeBreak 201 NCT04933695 | II | sotorasib | monotherapy first line (st. IV, TPS <1% and/or comut. STK11) | ongoing | [52] |
CodeBreak 101 NCT04185883 | Ib/II | sotorasib | EGFR inh, SHP2 inh, mTOR inh, CDK inh. Chemotherapy, ICIs, etc. | Ongoing | [60] |
KRYSTAL-1 NCT03785249 | I/II | adagrasib | monotherapy/afatinib, pembrolizumab, cetuximab | mPFS 6.5 months mOS 12.6 months FDA Approval | [62,63,64,67] |
KRYSTAL-12 NCT04685135 | III | adagrasib | monotherapy vs. docetaxel | ongoing | [68,69] |
KRYSTAL-7 NCT04613596 | II/III | adagrasib | pembrolizumab/pembrolizumab + adagrasib vs. pembrolizumab + chemotherapy (first line) | ongoing | [70] |
KRYSTAL-14 NCT04975256 | I/Ib | adagrasib | BI 1701963 (SOS inhibitor) | completed | |
KRYSTAL-2 NCT04330664 | I/II | adagrasib | TNO155 (SHP2 inhibitor) | ongoing | |
KRYSTAL-16 NCT05178888 | I/Ib | adagrasib | palbociclib (CDK4/6 inh.) | ongoing | |
NCT04449874 | I | GDC-6036 | monotherapy/ bevacizumab, atezolizumab, cetuximab, erlotinib, etc. | ongoing | [71,72] |
NCT04585035 | I/II | D-1553 | monotherapy/other agents | ongoing | [73] |
KontRASt-01 NCT04699188 | I/II | JDQ443 | monotherapy/ TNO155, tislelizumab | ongoing | |
NCT05009329 | I/II | JAB-21822 | monotherapy | ongoing | |
NCT04956640 | I | LY3537982 | monotherapy/ abemaciclib, cetuximab, pembrolizumab, chemotherapy, etc. | ongoing | |
NCT05462717 | I/Ib | RMC-6291 | monotherapy | ongoing |
Trial | Phase | KRAS Inhibitor | Combinations | Status/ Outcomes | References |
---|---|---|---|---|---|
NCT03634982 | I | RMC-4630 (SHP2 Inhibitor) | monotherapy | completed | [87] |
NCT03114319 | I | TNO155 (SHP2 Inhibitor) | monotherapy | ongoing | [87] |
NCT04111458 | I | BI 1701963 (SOS1 Inhibitor) | monotherapy/ trametinib (MEK Inh.) | ongoing | [87] |
NCT03284502 | I | belvarafenib (RAF Inh.) | cobimetinib, cetuximab | ongoing | [88,89,90,91] |
NCT01859026 | I | binimetinib (MEK Inh.) | erlotinib | completed | [88,89,90,91] |
NCT01986166 | I | cobimetinib (MEK Inh.) | duligotuzumab (EGFR/HER3 Inh.) | completed | [88,89,90,91] |
RAMP203 NCT05074810 | I/II | Avutometinib [VS-6766] (RAF–MEK Inhibitor) | sotorasib | ongoing | [92] |
RAMP204 NCT05375994 | I/II | Avutometinib [VS-6766] (RAF–MEK Inhibitor) | adagrasib | ongoing | [92] |
NCT04418167 | I | JSI-1187-01 (ERK Inhibitor) | monotherapy/ dabrafenib (BRAF Inh.) | ongoing | |
NCT04073680 | I/II | serabelisib (PI3K Inhibitor) | canagliflozin (SGLT2 Inh.) | completed | [94,95,96] |
NCT04586270 | I | TAS0612 (AKT Inhibitor) | monotherapy | ongoing | [94,95,96] |
TORCMEK NCT02583542 | I/II | AZD2014 (mTOR Inhibitor) | selumetinib (MEK Inh.) | completed | [94,95,96] |
NCT01951690 | II | defactinib (FAK Inhibitor) | monotherapy | completed | [99] |
GALAXY 2 NCT01798485 | III | ganetespib (HSP90 Inhibitor) | docetaxel vs. docetaxel alone | terminated (futility) | [106] |
NCT01892046 | I | SNX-5422 (HSP90 Inhibitor) | chemotherapy | completed | [107] |
Trial | Phase | KRAS Inhibitor | Combinations | Status/ Outcomes | References |
---|---|---|---|---|---|
NCT05737706 | I/II | MRTX1133 (KRAS-G12D Inh.) | monotherapy | ongoing | [141] |
V941-001 NCT03948763 | I | V941 (mRNA cancer vaccine) | monotherapy/pembrolizumab | completed | [144] |
NCT04735068 | II | hydroxychloroquine (autophagy inhibitor) | binimetinib (MEK Inh.) | ongoing | [145] |
CANOPY-N NCT03968419 | II | canakinumab (anti-IL-1β agent) | monotherapy/pembrolizumab | terminated (low enrollment) | [149,150,151] |
CHORUS NCT04905316 | II | canakinumab (anti-IL-1β agent) | durvalumab, chemoradiation | ongoing | [149,150,151] |
CANOPY-2 NCT03626545 | III | canakinumab (anti-IL-1β agent) | docetaxel vs. placebo + docetaxel | terminated (lack of efficacy) | [149,150,151] |
NCT04691817 | I/II | tecilizumab (IL-6 Inhibitor) | atezolizumab | ongoing | [149,150,151] |
NCT04940299 | II | tecilizumab (IL-6 Inhibitor) | nivolumab—ipilimumab | ongoing | [149,150,151] |
Pathway | Target | Inhibitor | References |
---|---|---|---|
Upstream signaling pathway | EGFR | erlotinib | [61] |
SHP2 | RMC-4630 TNO-155 | [87] | |
SOS 1 | BI 1701963 | [87] | |
Downstream signaling pathway MAPK pathway (RAF–MEK–ERK) | RAF | belvarafenib | [88,89,90,91] |
MEK RAF–MEK | binimetinib cobimetinib VS-6766 | [88,89,90,91] [92] | |
ERK | JSI-1187-01 | ||
Downstream signaling pathway PI3K–AKT–mTOR pathway | PI3K | BKM120 serabelisib XL147 | [94,95,96] |
AKT | TAS0612 | [94,95,96] | |
mTOR | AZD2014 | [94,95,96] | |
Other pathways | FAK | defactinib | [99] |
HSP90 | ganetespib SNX-5422 | [105,106] [107] | |
CDK 4/6 | palbociclib | [74,108,109,110] | |
DDR1 | |||
YB-1—RSK | LJI308 | ||
Immune system | ICIs | nivolumab atezolizumab | [113] [115] |
Metabolic rewiring | autophagy | hydroxychloroquine | [145] |
FASN | TVB-2640 | [146] | |
Tumor microenvironment (TME) | IL-1β IL-6 | canakinumab tecilizumab | [148,149,150,151] |
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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Karachaliou, A.; Kotteas, E.; Fiste, O.; Syrigos, K. Emerging Therapies in Kirsten Rat Sarcoma Virus (+) Non-Small-Cell Lung Cancer. Cancers 2024, 16, 1447. https://doi.org/10.3390/cancers16081447
Karachaliou A, Kotteas E, Fiste O, Syrigos K. Emerging Therapies in Kirsten Rat Sarcoma Virus (+) Non-Small-Cell Lung Cancer. Cancers. 2024; 16(8):1447. https://doi.org/10.3390/cancers16081447
Chicago/Turabian StyleKarachaliou, Anastasia, Elias Kotteas, Oraianthi Fiste, and Konstantinos Syrigos. 2024. "Emerging Therapies in Kirsten Rat Sarcoma Virus (+) Non-Small-Cell Lung Cancer" Cancers 16, no. 8: 1447. https://doi.org/10.3390/cancers16081447