Al Bitar S, El-Sabban M, Doughan S, Abou-Kheir W. Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond. World J Gastroenterol 2023; 29(9): 1395-1426 [PMID: 36998426 DOI: 10.3748/wjg.v29.i9.1395]
Corresponding Author of This Article
Wassim Abou-Kheir, MSc, PhD, Associate Professor, Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Bliss St, Beirut 1107-2020, Lebanon. wa12@aub.edu.lb
Research Domain of This Article
Biochemistry & Molecular Biology
Article-Type of This Article
Review
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Mar 7, 2023; 29(9): 1395-1426 Published online Mar 7, 2023. doi: 10.3748/wjg.v29.i9.1395
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
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
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
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
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
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
Citation: Al Bitar S, El-Sabban M, Doughan S, Abou-Kheir W. Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond. World J Gastroenterol 2023; 29(9): 1395-1426