Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond

Table 1 Agents targeting epidermal growth factor receptors and downstream molecules under clinical investigation for the treatment of drug-resistant and metastatic colorectal cancer

Agent	Targeted molecule	Condition	Study phase	Clinical trial identifier
Erlotinib	EGFR	First-line treatment for mCRC	Phase III	NCT01229813
Futuximab/Modotuximab (Sym-004)	EGFR	mCRC	Phase II	NCT02083653
Gefitinib	EGFR	Refractory CRC	Phase I/II	NCT00242788
Afatinib	EGFR	Refractory mCRC	Phase II	NCT01919879
		Advanced CRC	Phase II	NCT00801294
		mCRC	Phase II	NCT01152437
Dabrafenib (GSK2118436)	BRAF	mCRC	Phase II	NCT03668431
		mCRC	Phase II	NCT03428126
BMS-908662	BRAF	K-RAS/BRAF-mutated CRC	Phase I/II	NCT01086267
Encorafenib	Wild-type and BRAF V600E	Previously untreated BRAF-mutant mCRC	Phase II	NCT03693170
Vemurafenib	Mutated BRAF V600E	BRAF V600E mutated advanced CRC	Phase II	NCT03727763
PX-866	PI3K	mCRC	Phase I/II	NCT01252628
Gedatolisib	PI3K/mTOR	KRAS/NRAS-wild-type mCRC	Phase II	NCT01925274
		mCRC	Phase I/II	NCT01937715
Temsirolimus CCI-770	mTOR	KRAS-mutated mCRC	Phase II	NCT00827684
		Cetuximab-refractory CRC	Phase I	NCT00593060
Everolimus (RAD001)	mTOR	mCRC	Phase II	NCT01387880
		mCRC	Phase I/II	NCT01058655
		Advanced mCRC	Phase I/II	NCT01139138
		Refractory mCRC	Phase I	NCT01154335
MK-2206	AKT	Advanced CRC	Phase II	NCT01333475
Napabucasin (BBI608)	STAT3	Previously treated mCRC	Phase III	NCT03522649
Cobimetinib	MAPK	mCRC	Phase III	NCT02788279
Selumetinib	MEK	mCRC	Phase II	NCT00514761
Binimetinib	MEK	Previously untreated BRAF-mutant mCRC	Phase II	NCT03693170
Neratinib	EGFR/HER2/4	KRAS/NRAS/BRAF/PIK3CA-wild-type mCRC	Phase II	NCT03457896
Sapitinib (AZD-8931)	EGFR/HER2/3	mCRC	Phase II	NCT01862003
Duligotuzumab (MEHD7945A)	EGFR/HER3	KRAS-mutated mCRC	Phase II	NCT01652482
Trastuzumab	HER2	First-line HER2-positive mCRC	Phase III	NCT05253651
Tucatinib	HER2	First-line HER2-positive mCRC	Phase III	NCT05253651
Disitamab Vedotin	HER2	HER2-positive advanced CRC	Phase II	NCT05493683
		HER2-expressing mCRC	Phase II	NCT05333809
Trastuzumab-emtansine	HER2	HER2-positive mCRC progressing after trastuzumab and lapatinib	Phase II	NCT03418558

EGFR: Epidermal growth factor receptor; mCRC: Metastatic colorectal cancer; PI3K: Phosphoinositide 3-kinases; mTOR: Mammalian target of rapamycin; STAT3: Signal transducer and activator of transcription 3; AKT: Protein kinase B; MAPK: Mitogen-activated protein kinases; MEK: Mitogen-activated extracellular signal-regulated kinase; HER2: Human epidermal growth factor receptor 2.

Table 2 Agents targeting vascular endothelial growth factor/vascular endothelial growth factor receptor under clinical investigation for the treatment of drug-resistant and metastatic colorectal cancer

Agent	Targeted molecule	Condition	Study phase	Clinical trial identifier
Vanucizumab	VEGF-A/angiopoietin-2	mCRC	Phase II	NCT02141295
Sorafenib	VEGFR	mCRC	Phase II	NCT03251612
		Previously treated mCRC	Phase II	NCT01471353
		mCRC	Phase II	NCT00826540
		KRAS-mutated mCRC	Phase II	NCT01715441
Bevacizumab	VEGF	Untreated mCRC	Phase II	NCT02141295
		Advanced CRC	Phase II	NCT02487992
Linifanib ABT-869	VEGFR	Advanced CRC	Phase II	NCT00707889
Vatalanib	VEGFR	mCRC	Phase III	NCT00056446
		mCRC	Phase III	NCT00056459
Famitinib	VEGFR2/3	Advanced CRC	Phase II	NCT01762293
Cediranib	VEGFR2	First-line mCRC	Phase III	NCT00399035
Semaxanib	VEGFR	mCRC	Phase III	NCT00004252
		Advanced CRC	Phase I/II	NCT00005818
Nintedanib	VEGFR	Refractory mCRC	Phase III	NCT02149108
Ramucirumab	VEGFR2	Chemotherapy refractory mCRC	Phase III	NCT03520946
Apatinib	VEGFR2	Refractory CRC	Phase II	NCT03190616
		mCRC	NA	NCT03743428
		End-stage CRC	Phase II	NCT02829385
Brivanib	VEGFR2	KRAS-wild-type mCRC	Phase III	NCT00640471
Regorafenib	VEGFR1/2/3	Later-lines treatment of mCRC	Phase III	NCT05328908
		mCRC	Phase III	NCT05425940
Surufatinib	VEGFR1/2/3	Advanced CRC	Phase II	NCT05372198
Lenvatinib	VEGFR1/2/3	mCRC	Phase III	NCT04776148
Fruquitinib	VEGFR tyrosine kinase	Non-MSI-H/dMMR mCRC	Phase II	NCT04866862
Vandetanib	VEGF/VEGFR	mCRC	Phase I	NCT00532090
		mCRC	Phase II	NCT00500292
		Advanced CRC	Phase I	NCT00496509

VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; mCRC: Metastatic colorectal cancer; MSI: Microsatellite instability; dMMR: mismatch repair deficient.

Table 3 Agents targeting mesenchymal epithelial transition factor receptor under clinical investigation for the treatment of colorectal cancer and metastatic colorectal cancer

Agent	Targeted molecule	Condition	Study phase	Clinical trial identifier
Savolitinib	MET	mCRC	Phase II	NCT03592641
Tivantinib	MET	mCRC	Phase I/II	NCT01075048
Onartuzumab	MET	CRC	Phase II	NCT01418222
Cabozantinib	MET/RET/VEGFR-2	CRC	Phase I	NCT02008383
		mCRC	Phase I	NCT03798626
		Refractory mCRC	Phase II	NCT03542877
Rilotumumab	HGF	KRAS wild-type mCRC	Phase I/II	NCT00788957

MET: Mesenchymal epithelial transition factor receptor; mCRC: Metastatic colorectal cancer; CRC: Colorectal cancer; VEGFR: Vascular endothelial growth factor receptor; HGF: Hepatocyte growth factor; RET: Rearranged during transfection.

Table 4 Agents targeting immune checkpoints under clinical investigation for the treatment of drug-resistant and metastatic colorectal cancer

Agent	Targeted molecule	Condition	Study phase	Clinical trial identifier
Camrelizumab	PD-1	Non-MSI-H/dMMR mCRC	Phase II	NCT04866862
		mCRC	Phase II	NCT03912857
Tislelizumab	PD-1	HER2-Positive Advanced CRC	Phase II	NCT05493683
Nivolumab	PD-1	Later-lines treatment of mCRC	Phase III	NCT05328908
		Advanced CRC	Phase I	NCT02991196
		Metastatic MSS CRC	Phase I	NCT03993626
		mCRC	Phase II	NCT04166383
Pembrolizumab (MK-3475)	PD-1	MSI-H/dMMR CRC	Phase III	NCT05239741
		mCRC	Phase III	NCT04776148
		MMR-proficient mCRC	Phase II	NCT03519412
		HER2-expressing mCRC	Phase II	NCT03631407
		HER2-expressing mCRC	Phase II	NCT05333809
PDR-001	PD-1/PD-L1	mCRC	Phase I	NCT03081494
		First-line mCRC	Phase I	NCT03176264
Toripalimab	PD-1/PD-L1	mCRC	Phase II	NCT03927898
Avelumab	PD-1/PD-L1	mCRC	Phase II	NCT03150706
		mCRC	Phase II	NCT03258398
Atezolizumab	PD-L1	mCRC	Phase III	NCT05425940
		mCRC	Phase III	NCT02788279
		First-line mCRC	Phase II	NCT02291289
		Refractory CRC	Phase II	NCT02873195
Relatlimab	LAG-3	Later-lines treatment of mCRC	Phase III	NCT05328908
Tremelimumab	CTLA-4	mCRC	Phase I/II	NCT03202758
		mCRC	Phase II	NCT03122509
		mCRC	Phase II	NCT03428126
		mCRC	Phase II	NCT03435107

PD-1: Programmed death-1; PD-L1: Programmed death ligand-1; mCRC: metastatic colorectal cancer; MSI-H/dMMR: Microsatellite instability-high/mismatch repair deficient; MSS: Microsatellite stable; HER2: Human epidermal growth factor receptor 2; LAG-3: Lymphocyte activation gene 3; CTLA-4: Cytotoxic T lymphocyte-associated antigen 4.

Table 5 Agents targeting other pathways under clinical investigation for the treatment of drug-resistant and metastatic colorectal cancer

Agent	Targeted molecule	Condition	Study phase	Clinical trial identifier
CB-103	Notch	Resistant to oxaliplatin or irinotecan-based therapy advanced or mCRC	Phase I/II	NCT03422679
RO4929097	Notch	mCRC	Phase II	NCT01116687
WNT974	Wnt	BRAF-mutant mCRC	Phase I/II	NCT02278133
FOXY-5	Wnt	mCRC	Phase I	NCT02020291
LGK974	Wnt	BRAF mutant CRC	Phase I	NCT01351103
Vismodegib (GDC-0449)	Hedgehog	First-line therapy mCRC	Phase II	NCT00636610
		mCRC	Phase II	NCT00959647
LDE225	Hedgehog	mCRC	Phase I	NCT01576666
NIS793	TGF	Advanced CRC	Phase I	NCT02947165
LY3200882	TGF	Advanced chemotherapy -resistant CRC with an activated TGF-beta Signature	Phase I/II	NCT04031872
Ganitumab	IGF-1R	KRAS wild-type mCRC	Phase I/II	NCT00788957
		KRAS-mutant mCRC	Phase II	NCT00813605
Dalotuzumab (MK-0646)	IGF-1R	mCRC	Phase II	NCT00614393
Cixutumumab (IMC-A12)	IGF-1R	mCRC resistant to EGFR therapy	Phase II	NCT00503685

Wnt: Wingless-related integration site; mCRC: Metastatic colorectal cancer; TGF: Transforming growth factor; IGF-1R: Insulin growth factor receptor-1; EGFR: Epidermal growth factor receptor.

Table 6 Combination of targeted therapies under clinical investigation for the treatment of drug-resistant and metastatic colorectal cancer

Agents	Targeted molecule (s)	Condition	Study phase	Clinical trial identifier
Encorafenib + Binimetinib + Cetuximab	Wild type plus BRAF V600E and MEK, EGFR	Previously untreated BRAF-mutant mCRC	Phase II	NCT03693170
Tucatinib + Trastuzumab	HER2	First-line HER2-positive mCRC	Phase III	NCT05253651
Disitamab + Vedotin + Tislelizumab	HER2 and PD-1	HER2-positive advanced CRC	Phase II	NCT05493683
Vanucizumab + Bevacizumab	VEGF-A/angiopoietin-2 and VEGF	mCRC	Phase II	NCT02141295
Regorafenib + Nivolumab	VEGFR1/2/3 and PD-1	Later-lines treatment of mCRC	Phase III	NCT05328908
Lenvatinib + Pembrolizumab	VEGFR1/2/3 and PD-1	mCRC	Phase III	NCT04776148
Fruquitinib + Camrelizumab	VEGFR tyrosine kinase and PD-1	Non-MSI-H/dMMR mCRC	Phase II	NCT04866862
Disitamab + Vedotin + Pembrolizumab	HER2 and PD-1	HER2-expressing mCRC	Phase II	NCT05333809
Cobimetinib + Atezolizumab	MAPK and PD-L1	mCRC	Phase III	NCT02788279
Cetuximab + Vemurafenib	EGFR and mutated BRAF V600E	BRAF V600E Mutated Advanced CRC	Phase II	NCT03727763
Penpulimab + Anlotinib	PD-1 and VEGFR1/2/3	Refractory mCRC	Phase II	NCT04970914
Favezelimab	LAG-3 and PD-1	Previously treated metastatic PD-L1 positive CRC	Phase III	NCT05064059
MEN1611 + Cetuximab	PI3K and EGFR	mCRC	Phase I/II	NCT04495621
Encorafenib + Cetuximab + Pembrolizumab	BRAF V600E, as well as wild-type BRAF, EGFR, andPD-1	Previously untreated mCRC	Phase II	NCT05217446
RXC004 + Nivolumab	Porcupine (wnt activator) and PD1	RNF43 or RSPO aberrated, metastatic, MSS CRC after progression on SOC	Phase II	NCT04907539
Regorafenib + Pembrolizumab	VEGFR1/2/3PD1	Advanced or mCRC	Phase I/II	NCT03657641
Isatuximab + Atezolizumab	Epitope on CD38, and PD-L1	mCRC	Phase I/II	NCT03555149
Atezolizumab + Selicrelumab + Bevacizumab	PD-L1, CD40 antigen, and VEGF	mCRC	Phase I/II	NCT03555149
Atezolizumab + Idasanutlin	PD-L1 and MDM2	mCRC	Phase I/II	NCT03555149
Atezolizumab + Regorafenib	PD-L1 andVEGFR1/2/3	mCRC	Phase I/II	NCT03555149
Olaparib (MK-7339) + Bevacizumab	PARP and VEGF	Unresectable or mCRC	Phase III	NCT04456699
Nivolumab + Ipilimumab	PD-1 andCTLA-4	dMMR and/or MSI mCRC resistant to anti-PD1 monotherapy	Phase II	NCT05310643
Nivolumab + Ipilimumab	PD-1 and CTLA-4	dMMR and/or MSI mCRC	Phase II	NCT04730544
Surufatinib + Sintilimab	VEGFR1/2/3 and PD-1	Advanced MSS-Type CRC	Phase II	NCT04764006
Camrelizumab + Apatinib	PD-1 and VEGFR-2	Advanced CRC	Phase I/II	NCT04067986
Fruquintinib + Tislelizumab + Stereotactic ablative radiotherapy	VEGFR1/2/3 and PD-1	mCRC	Phase II	NCT04948034
Avelumab + Cetuximab + mFOLFOXIRI	PD-1/PD-L1 and EGFR	Unresectable mCRC	Phase II	NCT04513951
Geptanolimab (GB226) + Fruquintinib	PD-1 and VEGFR1/2/3	mCRC	Phase I	NCT03977090
Selinexor + Pembrolizumab	Exportin 1 and PD-1	Previously treated mCRC with RAS mutations	Phase II	NCT04854434
Panitumumab + Rilotumumab	EGFR and HGF	wild-type KRAS mCRC	Phase I/II	NCT00788957
Panitumumab + Ganitumab	EGFR and IGF-1R	wild-type KRAS mCRC	Phase I/II	NCT00788957

MEK: Mitogen-activated extracellular signal-regulated kinase; EGFR: Epidermal growth factor receptor; mCRC: Metastatic colorectal cancer; HER2: Human epidermal growth factor receptor 2; PD-1: Programmed death-1; PD-L1: Programmed death ligand-1; VEGF-A: Vascular endothelial growth factor-A; VEGFR: Vascular endothelial growth factor receptor; MSI-H/dMMR: Microsatellite instability-high/mismatch repair deficient; MSS: Microsatellite stable; MAPK: mitogen-activated protein kinases; LAG-3 Lymphocyte activation gene 3; PI3K: Phosphoinositide 3-kinases; RNF43: Ring Finger Protein 43; RSPO: R-spondin; SOC: Standard of Care; PARP: Poly ADP ribose polymerase; CTLA-4: Cytotoxic T lymphocyte-associated antigen 4; HGF: Hepatocyte growth factor; IGF-1R: Insulin growth factor receptor-1.