Targeting Mutant KRAS in Pancreatic Cancer: Futile or Promising?
Abstract
:1. Introduction
2. KRAS
3. Direct Targeting
4. Indirect Targeting
4.1. Targeted Therapies Engaging Upstream of KRAS
4.2. Disruption of Signaling Cascades Downstream of KRAS
5. Immune Modulatory Perspective
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Drug | Sponsor | Target | Binding Site | Phase | Indication | n= |
---|---|---|---|---|---|---|
AMG-510NCT03600883 | Amgen | KRASG12C | switch-II | I/II | solid tumors | 533 a |
AMG-510NCT04303780 | Amgen | KRASG12C | switch-II | III | advanced mNSCLC | 650 b |
AMG-510 (with anti-PD1, MEKi, SHP2i, pan-ErbBi) NCT04185883 | Amgen | KRASG12C | switch-II | I | advanced solid tumors | 430 a |
MRTX849 (alone and with pembrolizumab, cetuximab or afatinib) NCT03785249 | Mirati Therapeutics Inc. | KRASG12C | switch-II | I/II | advanced solid tumors | 200 a |
MRTX849 (with TNO155) NCT04330664 | Mirati Therapeutics Inc. | KRASG12C | switch-II | I/II | advanced solid tumors | 148 a |
ARS-3248/ JNJ-74699157NCT04006301 | Janssen | KRASG12C | switch-II | I/II | advanced solid tumors (NSCLC; colon cancer) | 10/140 c |
LY3499446 (alone and with abemaciclib, cetuximab or erlotinib) NCT04165031 | Eli Lilly and Company | KRASG12C | switch-II | I/II | advanced solid tumors (NSCLC; colon cancer) | 230 a |
BI-1701963 (alone and with trametinib) NCT04111458 | Boehringer Ingelheim | KRASmut (KRASwt) | switch-I/II specifically SOS1:KRAS | I/II | solid tumors | 140 a |
Drug | Sponsor | Target | Phase | Indication | n= |
---|---|---|---|---|---|
RMC-4630 NCT03634982 | Revolution Medicines, Inc. | SHP2 | I | advanced solid tumors (with specific genotypic aberrations leading to RAS pathway hyperactivation) | 240 a |
RMC-4630 (with cobimetinib) NCT03989115 | Revolution Medicines, Inc./Sanofi | SHP2 | Ib/II | advanced solid tumors (with specific genotypic aberrations leading to RAS pathway hyperactivation) | 144 a |
RMC-4630 (with pembrolizumab) NCT04418661 | Sanofi/Revolution Medicines, Inc. | SHP2 | I | advanced solid tumors (with specific genotypic aberrations leading to RAS pathway hyperactivation) | 24 a |
TNO155 (with MRTX849) NCT04330664 | Mirati Therapeutics Inc./Novartis | SHP2 | I/II | advanced solid tumors (KRASG12C) | 148 a |
JAB-3068 NCT03565003 | Jacobio Pharmaceuticals Co., Ltd. | SHP2 | I/IIa | advanced solid tumors | 120 a |
Drug | Sponsor | Target | Phase | Indication | n= |
---|---|---|---|---|---|
Belvarafenib (with Cobimetinib) NCT03284502 | Hanmi Pharmaceutical Company Limited | RAF | I | advanced solid tumors | 272 a |
LXH254 (alone and with Spartalizumab) NCT02607813 | Novartis Pharmaceuticals | RAF | I | advanced solid tumors (with MAPK alterations) | 152 a |
RO5126766 (with VS-6063) NCT03875820 | Institute of Cancer Research, UK/Verastem, Inc./Chugai Pharmaceutical | dual RAF/MEK | I | advanced RAS mutant solid tumors | 80 a |
RO5126766 (alone and with Everolismus) NCT02407509 | Royal Marsden NHS Foundation Trust/Verastem, Inc./Chugai Pharmaceutical | dual RAF/MEK | I | solid tumors | 94 a |
Trametinib (with Navitoclax) NCT02079740 | National Cancer Institute (NCI) | MEK | I/II | Advanced solid tumors (incl. stage III/IV pancreatic cancer) | 130 a |
Trametinib (with Hydroxychloroquine) NCT03825289 | University of Utah/Novartis Pharmaceuticals | MEK | I | Advanced pancreatic cancer | 33 a |
Binimetinib (with Avelumab and/or Talazoparib) NCT03637491 | Pfizer | MEK | Ib/II | advanced solid tumors (with RAS-mutation) pancreatic cancer | 122 a |
MK-8353 (with Pembrolizumab) NCT02972034 | Merck Sharp & Dohme Corp | ERK1/2 | I | advanced solid tumors | 96 a |
JSI-1187 (alone and with Dabrafenib) NCT04418167 | JS InnoPharm, LLC | ERK1/2 | I | advanced solid tumors (with MAPK pathway mutations) | 124 a |
LY3214996 (alone or with Abemaciclib or Nab-Paclitaxel and Gemcitabine or Encorafenib and Cetuximab) NCT02857270 | Eli Lilly and Company | ERK1/2 | I | advanced solid tumors (incl. metastatic pancreatic ductal adenocarcinoma) | 272 a |
LY3214996 (alone and with Hydroxychloroquine) NCT04386057 | Dana-Farber Cancer Institute/Eli Lilly and Company | ERK1/2 | I | Pancreatic Cancer | 52 a |
Gedatolisib (with Palbociclib) NCT03065062 | Dana-Farber Cancer Institute/Pfizer | PI3K/mTOR | I | advanced solid tumors (incl. pancreatic cancer) | 96 a |
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Nollmann, F.I.; Ruess, D.A. Targeting Mutant KRAS in Pancreatic Cancer: Futile or Promising? Biomedicines 2020, 8, 281. https://doi.org/10.3390/biomedicines8080281
Nollmann FI, Ruess DA. Targeting Mutant KRAS in Pancreatic Cancer: Futile or Promising? Biomedicines. 2020; 8(8):281. https://doi.org/10.3390/biomedicines8080281
Chicago/Turabian StyleNollmann, Friederike Inga, and Dietrich Alexander Ruess. 2020. "Targeting Mutant KRAS in Pancreatic Cancer: Futile or Promising?" Biomedicines 8, no. 8: 281. https://doi.org/10.3390/biomedicines8080281