Bromodomain and extra-terminal inhibitors emerge as potential therapeutic avenues for gastrointestinal cancers

Table 1 Preclinical models of Bromodomain and extra-terminal inhibitors in gastrointestinal cancers

GI cancers models	BET inhibitors	Combination with	Targets	Pathway/mechanism	Ref.
CRC	JQ-1	5-FU	DR5	Apoptosis	[49]
	JQ-1	Bortezomib	MYC, FOXM1	G2/M arrest	[47]
	JQ-1	-	HGF, MET	Cancer-associated fibroblasts	[98]
	Apabetalone	-	APOA1	Intracellular cholesterol metabolism	[99]
	JQ-1	BEZ235 (PI3K/mTOR inhibitor)	RTKs	Overcome resistance to PI3K/mTOR inhibition	[40]
	JQ-1	Sulforaphane (HDAC3 inhibitor)	ERCC2	Nucleotide excision repair pathway	[48]
	I-BET151, bromosporine	-	BRD4, SNAIL, SLUG	EMT	[100]
SMAD4-defificient CRC	OTX-015	-	MYC	MYC-p21 axis, G1 cell cycle arrest	[54]
Colon cancer	JQ-1	-	Nkd2, β-catenin, miR-21	Wnt/β-catenin signaling, apoptosis	[45]
Gastric and colon cancer	JQ-1	Arsenic sulfide	NFATs, c-MYC	Mitochondrial pathway induced cell apoptosis	[51]
PDAC	JQ-1	-	HMGA2	Block growth of chemoresistant cells	[55]
	JQ-1	Olaparib (PARP inhibitor)	BRD2/4, Ku80, RAD51	DNA damage	[60]
	JQ-1	SAHA (HDAC inhibitor)	p57	Cell death	[61]
	JQ-1	Gemcitabine	HMGCS2, APOC1	DNA damage and apoptosis	[62]
	CPI203	-	MYC, GLI, SHH	SHH-GLI signaling pathway, cell cycle progression	[24]
Pancreatic cancer	JQ-1, OTX-015	Quercetin	BRD4(JQ-1) and hnRNPA1(Quercetin)	Apoptosis	[63]
KDM6A null pancreatic cancer	JQ-1	-	MYC, p63, RUNX3	Reverse squamous differentiation	[101,102]
Liver cancer	JQ-1	-	BRD4, E2F2	BRD4-E2F2-cell cycle regulation axis,	[34]
	JQ-1	-	PD-L1, PD-L2	PD-1/PD-L1 signaling	[71]
HCC	JQ-1, I-BET762	Anti-PD-L1 Ab	BRD4, C/EBPβ, p300	Suppress M-MDSCs, enhance PD-L1 blockade efficacy	[73]
	JQ-1	-	MYC	Impair mitochondrial respiration and glycolysis, induce apoptosis	[66]
	Hjp-6-171	GSK3β inhibitor (CHIR-98014)	β-catenin, NOTUM	WNT pathway	[68]
	SF1126 (Pan PI3K/BRD4 Inhibitor)	Sorafenib	BRD4, c-MYC	Ras/Raf/MAPK, PI3K/AKT/mTOR pathways	[90]
	JQ-1	-	PES1	Cell proliferation, glycolysis	[35]
	JQ-1	Flavopiridol	Mcl-1	Apoptosis	[67]
	JQ-1, OTX-015	-	SMARCA4	Down-regulate migration related genes	[65]
CCA2	JQ-1	PI3K/mTOR inhibitors	c-Myc, YAP	Overcome resistance to PI3K/mTOR inhibition	[64]
Gastric cancer	JQ-1	-	BRD4, E2F	E2F/miR-106b-5p/p21 axis, cellular senescence	[32]
	JQ-1	-	RUNX2	RUNX2/NID1 signaling, site-specific chromatinremodeling	[75]
	JQ1, PNZ5	-	c-MYC	Apoptosis	[33,74]
	iBET-151	Paclitaxel	RTK	G1 cell cycle arrest	[79]
	AZD5153	-	Sirt5, Mus81	Sirt5/Mus81/ZEB1 axis, inhibit metastasis	[76]
GAC	JQ-1	CA3 (YAP inhibitor)	c-MYC	Gal3/RalA/YAP1/c-MYC axis	[78]

CRC: Colorectal cancer; PDAC: Pancreatic ductal adenocarcinoma; HCC: Hepatocellular carcinoma; CCA: Cholangiocarcinoma; GAC: Gastric adenocarcinoma; 5-FU: 5-fluorouracil; c-MYC: Cellular-myelocytomatosis.

Table 2 Clinical trials of Bromodomain and extra-terminal inhibitors in gastrointestinal cancers (Trial ID on www.clinicaltrials.gov)

Drug	Combination with	Condition	Status	Clinical phase	Trial ID
INCB054329	-	Solid Tumors and Hematologic Malignancy (CRPC, BC, HGSC, CRC, Ewing sarcoma, Pancreatic adenocarcinoma, AML, MDS, MF, MM)	Terminated due to PK variability	Phase I/II	NCT02431260
INCB057643	Gemcitabine; Paclitaxel; Rucaparib; Abiraterone; Ruxolitinib; Azacitidine	Solid Tumors (CRPC, BC, HGSC, CRC, Glioblastoma multiforme, Ewing sarcoma, Pancreatic adenocarcinoma, AML, MDS)	Terminated due to safety issues	Phase I/II	NCT02711137
AZD5153	Olaparib	Malignant Solid Tumors, Lymphoma, Ovarian Cancer, Breast Cancer, Pancreatic Cancer, Prostate Cancer	Active, not recruiting	Phase I	NCT03205176
I-BET762 (Molibresib, GSK525762)	Entinostat	Solid tumors (Advanced Malignant Solid Neoplasm, Refractory Malignant Solid Neoplasm, Refractory Pancreatic Carcinoma, Stage II/IIA/IIB/III/IV Pancreatic cancer AJCC v8, Unresectable Pancreatic Carcinoma) or Lymphomas	Withdrawn (Other-Protocol moved to Disapprove)	Phase I	NCT03925428
SF1126	-	Advanced Hepatocellular Carcinoma	Active, not recruiting	Phase I	NCT03059147