Emerging strategies to target RAS signaling in human cancer therapy

Chen, Kun; Zhang, Yalei; Qian, Ling; Wang, Peng

doi:10.1186/s13045-021-01127-w

Journal of Hematology & Oncology

Table 4 Potential molecules targeting RAS signaling in preclinical or clinical trials

From: Emerging strategies to target RAS signaling in human cancer therapy

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

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