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. 2021 Jul 23;14:116. doi: 10.1186/s13045-021-01127-w

Table 4.

Potential molecules targeting RAS signaling in preclinical or clinical trials

Targets Molecule Tumor Type/model RAS Mut Phase Status Notes Referencess
Target the upstream
FTase/GGTase Antroquinonol PDAC KRAS mut lnc Clinical I/II Recruiting Single agent NCT03310632
NSCLC NM Clinical I Completed Single agent NCT01134016
tipifarnib TC HNSCC SCC HRAS Clinical II Completed Single agent NCT02383927 [69]
UC HRAS Clinical II NM Single agent [70]
PDEδ Deltarasin Xenografted PDAC modelss KRAS Pre NA Single agent [75]
Deltazinones PDAC cell lines KRAS Pre NA Single agent [77]
Deltasonamides PDAC cell lines KRAS Pre NA Single agent [228]
NHTD Xenografted NSCLC models KRAS Pre NA Single agent [79]
STK19 ZT-12–037-01 (1a) Melanoma xenograft models NRAS Pre NA Single agent [86]
Chelidonine Melanoma xenograft models, cell lines NRAS Pre NA Single agent [87]
SHP2 SHP099 PDAC, NSCLC xenograft models KRAS Pre NA Single agent [84]
JAB-3068 NSCLC, HNC, ESC, Other solid tumors NM Clinical I/II Recruiting Single agent NCT03565003
JAB-3312 NSCLC, CRC, PDAC, BC, ESC KRAS G12 mut lnc Clinical I Recruiting Single agent NCT04045496
TNO155 NSCLC, CRC KRAS G12C Mut lnc Clinical I Recruiting Single agent NCT03114319
RMC-4630 PC, OVCA, OEC, ESC, NF1 KRAS G12 Mut lnc Clinical I Recruiting Single agent NCT03634982
Solid tumors KRAS mut lnc Clinical Ib/II Recruiting Comb with Cobimetinib NCT03989115
Target the downstream
RAF HM95573 Solid tumors KRAS, NRAS Clinical I Completed Single agent NCT03118817
RO5126766(VS-6766) NSCLC KRAS Clinical I Active, not recruiting Dual MEK/Raf inhibitor NCT03681483
NSCLC KRAS Clinical I Recruiting Comb with FAK inhibitor (VS-6063) NCT03875820
LGSOC KRAS Clinical II Recruiting Comb with FAK inhibitor (VS-6063) NCT04625270
LXH254 NSCLC, MM KRAS, NRAS Clinical Ib Recruiting Comb with MEK, ERK, or CD4/6 inhibitors NCT02974725
Lifirafenib MM, TC, OC, NSCLC, CRC, EC KRAS, NRAS Clinical I completed Single agent [131]
CCT3833 MM RAS Mut lnc Clinical I completed Single agent NCT02437227
MEK1/2 PD-0325901 NSCLC KRAS Clinical I/II Active, not recruiting Comb with CD4/6 inhibitor (Palbociclib) NCT02022982
NSCLC KRAS Clinical I/II Recruiting Comb with pan-HER inhibitor (Dacomitinib) NCT02039336
NSCLC, EC, CRC, OC, TC, PC, MM KRAS Clinical I/II Recruiting Comb with dual BRAF and EGFR, Inhibitor (BGB-283) NCT03905148
MEK162 NSCLC KRAS Clinical I/II Recruiting Comb with CDK4/6 inhibitor (Palbocicib) NCT03170206
NSCLC KRAS Clinical I/Ib Active, not recruiting Comb with EGFR inhibitor (Erlotinib) NCT01859026
PC CRC NSCLC MM KRAS NRAS Mut lnc Clinical I Completed Comb with PI3K inhibitor (BKM120) NCT01363232
Solid tumors KRAS NRAS Mut lnc Clinical I Completed comb with AKT inhibitor (BEZ235) NCT01337765
PC, NSCLC KRAS NRAS Clinical Ib/II Terminated Comb with PARP and PDL1 inhibitor (Talazoparib, Avelumab) NCT03637491
Cobimetinib NSCLC, CRC KRAS Clinical I Completed Comb with MEHD7945A NCT01986166
Trametinib NSCLC KRAS, NRAS Mut lnc Clinical II Completed Single agent NCT01362296
mCRC KRAS Mut lnc Clinical Ib/II Terminated Comb with CDK4/6 inhibitor (ribociclib) NCT02703571
NSCLC, PC KRAS Clinical Ib/II Recruiting Comb with Bcl-2 inhibitor (Navitoclax) NCT02079740
Multiple Myeloma KRAS NRAS Mut lnc Clinical I Recruiting Comb with BRAF inhibitor (Dabrafenib) NCT03091257
NSCLC KRAS Mut lnc Clinical I/II Active, not recruiting Comb with PD1 inhibitor (Pembrolizumab) NCT03225664
MM NRAS Clinical Ib/II I/II Terminated Comb with ERBB3 inhibitor (CDX-3379) NCT03580382

Solid tumors

DTC

 NRAS lnc Clinical I NA Comb with VEGF inhibitor (Pazopanib) [13]
Selumetinib NSCLC KRAS Clinical II Withdrawn Comb with PDL1 inhibitor (durvalumab) NCT03004105
NSCLC KRAS Clinical I/II Recruiting Comb with EGFR inhibitor (Afatinib) NCT02450656
mCRC KRAS Mut lnc Clinical II Completed Comb with chemotherapy (Irinotecan) NCT01116271
NSCLC KRAS Mut lnc Clinical Ib/II Active, not recruiting Comb with mTOR inhibitor (AZD2014) NCT02583542
mCRC KRAS Clinical II Completed Comb with AKT inhibitor (MK-2206) NCT01333475
NSCLC KRAS Clinical III Active, not recruitingrecruiting Comb with chemotherapy (Docetaxel) NCT01933932
Pimasertib MM NRAS Clinical II Completed Single agent NCT01693068
FCN-159 MM NRAS Clinical I Recruiting Single agent NCT03932253
ERK1/2 ASN007 MM, CRC, NSCLC KRAS, NRAS Mut lnc Clinical I Completed Single agent NCT03415126
Ulixertinib Solid tumors KRAS, NRAS HRAS Mut lnc Clinical II Suspended Single agent NCT03698994
KO-947 Solid tumors KRAS, NRAS HRAS Mut lnc Clinical I Terminated Single agent NCT03051035
SCH772984 Pancreatic KRAS Pre NA Single agent [154]
Xenograft Models
AZD0364 NSCLC CRC Xenograft Models KRAS Pre NA Comb with MEK inhibitor (selumetinib) [157]
PI3K PF-05212384 NSCLC KRAS Mut Clinical I Terminated Comb with MEK inhibitor (PD-0325901) NCT01347866
BKM120 Solid tumors KRAS Mut lnc Clinical I Completed Comb with MEK inhibitor (GSK1120212) NCT01155453
GSK2126458 Solid tumors KRAS Mut lnc Clinical I Terminated Comb with MEK inhibitor (GSK1120212) NCT01248858
Pictilisib Solid tumors KRAS Mut lnc Clinical I Terminated Comb with MEK inhibitor (cobimetinib) NCT00996892
Akt MK2206 NSCLC KRAS Clinical I Completed Comb with MEK inhibitor (AZD6244) NCT01021748
CRC KRAS Clinical II Completed Comb with MEK inhibitor (AZD6244) NCT01333475
GSK2141795 AML KRAS/NRAS Mut Clinical II Terminated Comb with MEK inhibitor (Trametinib) NCT01907815
GSK2110183 Solid tumors KRAS Mut lnc Clinical I Completed Comb with MEK inhibitor (Trametinib) NCT01476137
mTOR TAK-228 SCLC KRAS Clinical II Completed Single agent NCT02417701
MK8669 NSCLC KRAS Clinical II Terminated Single agent NCT00818675
Temsirolimus mCRC KRAS Clinical II Completed Comb with chemotherapy (Irinotecan) NCT00827684
Everolimus mCRC KRAS Clinical II Completed Single agent NCT00419159
NSCLC KRAS Clinical I Completed Comb with Sorafenib NCT00933777
EC KRAS Clinical II Completed Single agent

NCT00870337

[184]
RNA interference
siRNA-Loaded nanoparticles NSCLC cell lines KRAS Pre NA Single agent [114]
AZD4785 NSCLC mCRC KRAS Clinical I Completed Single agent NCT03101839
siG12D LODERAZD4785 LAPCNSCLC, mCRC KRAS G12D Clinical I Completed Single agent [120]
iExosomes G12D PDAC KRAS G12D Clinical I Recruiting Single agent NCT03608631
siRNA
V941 Advanced PDAC, CRC, NSCLC KRAS Mut Clinical I Recruiting Single agent or Comb with Pembrolizumab NCT03948763
Target metabolic process
Chloroquine PDAC, MM xenograft models KRAS, NRAS Pre NA Comb with MEK inhibitor (Trametinib) [191]
PDAC xenograft KRAS Pre NA Comb with ERK inhibitor [190]
Models (SCH772984)
Other strategies
Anti-KRAS PC, GC, RC, GICA KRAS G12D Clinical I/II Suspended Single agent NCT03190941
G12 mTCR G12V Mut NCT03745326
PBL
CRISPR/Cas9 NSCLC xenograft modelsMODEL KRAS G12S Pre NA Single agent [118]
System Model
PROTACs NSCLC cell lines KRAS G12C Pre NA Single agent [194, 195]
NIH-3T3 KRAS G12V Pre NA dTAG system [198]
NIH-3T3 KRAS G12V Pre NA HaloPROTACs [197]
A549 HRAS Pre NA HaloPROTAC comb with [199]
KRAS G12S L-AdPROM
SW480 KRAS Pre NA PROTAC (PDEδ) [200]
NSCLC cell lines KRAS mut Pre NA PROTAC (TBK1) [201]

mCRC metastatic colorectal cancer, NSCLC non-small-cell lung carcinoma, PC pancreatic cancer, OVCA ovarian cancer; OEC, ovarian epithelial cancer, ESC esophageal carcinoma, NF1 neurofibromatosis type 1, GC gastric cancer, CC colon cancer, RC rectal cancer, UC urothelial carcinoma, GICA gastrointestinal cancer, EC endometrial cancer, PanIN pancreatic intra-epithelial neoplasia, LAPC locally advanced pancreatic cancer, MM malignant melanoma, PBL peripheral blood lymphocytes, Mut mutation, lnc include, means including patients with RAS mutation, NA, none. PROTACs PROteolysis TArgeting Chimeras