Narrowing the focus: Therapeutic cell surface targets for refractory triple-negative breast cancer

Table 1 Pre-clinical studies targeting the cell-surface of triple negative breast cancer

Gene, Protein	Protein type and function1	TNBC expression2	Normal tissue expression	Drug3	Studies4	Ref.
ANTXR1 (TEM8), Anthrax toxin receptor 1	SPT1MP, integrin-like; Attachment, migration, progression	Protein, n = 23, 100% stromal; very low in surrounding NB. Protein, BC tissues, n = 120, NB, n = 33, increased in invasive BC	6High: Gallbladder; Medium and low: Broadly expressed	CAR-T	Xenograft regression	[34-36]
ICAM1, Intercellular adhesion molecule-1	SPT1MP; Binds leukocyte adhesion protein LFA-1 (integrin αL/β2)	mRNA, n = 6 (cell lines), 60%; BC 25%. Protein, n = 6 (cell lines), increased expression	5High: Lung, kidney. Medium: Bone marrow and immune system, endometrium. Low: Cerebral cortex, colon, bladder, testis, fallopian tube	mAb: Enlimomab (murine mAb against the human ICAM1); TLipo: Lipocalin-2 siRNA payload	CAM assay; decreased xenograft angiogenesis	[37,38]
MELK, Maternal embryonic leucine zipper kinase	PMP, serine/threonine kinase. Cell cycle regulation, stem-cell self-renewal, apoptosis, splicing regulation, radiation resistance	mRNA, n = 59, increased relative to BC, n = 284 and NB (n = 105)	5High and medium: Broadly expressed	Ib: OTSSP167	Ib + radiation decreased xenograft growth	[39,40]
FZD7, Frizzled-7	MPMP, Wnt protein receptor. Possibly signals polarity during morphogenesis, differentiation	mRNA, n = 5, increased relative to BC, n = 14	5High and medium: Broadly expressed	shRNA against FZD7	Decreased xenograft growth	[41]
MMP14, Matrix metallo-proteinase-14	SPT1MP, Endopeptidase. Degrades extracellular matrix	ND, general increased in metastatic cancers	5Medium and low: Broadly expressed	Humanized Fab Ab	Decreased progression and metastasis of syngeneic tumors	[42]
MSLN, Mesothelin	Cell surface GPI anchor, secreted. Cell adhesion	Protein, n = 109, 34%. Protein, n = 99, 67% mRNA, n = 226, increased relative to BC, n-88	6Broadly very low to non-expressed. 7120 organs: (1) Lung, mesothelial cells, uterus; (2) Low in heart, kidney and placenta	ADC: RG7787, Ab fragment/pseudomonas exotoxin A. CAR-T (TNBC not tested)	Xenograft regression	[43-47]
GBP1, Guanylate-binding protein 1	Cell surface lipid anchor, secreted. Hydrolyzes GTP to GMP. Host protection against pathogens	mRNA, n = 1512, increased relative to BC, n = 1412 and NB, n = 3887	5Medium: Thyroid, appendix, small intestine. Low: Brain, tonsil, lung, GI tract, kidney, fallopian tube, endometrium, skin	None	Expression controlled by EGFR. Knockdown decreased cell growth	[48]
MST1R, Macrophage-stimulating protein receptor (RON)	SPT1MP, tyrosine kinase receptor. MST1 ligand. Proliferation, survival, migration, differentiation	Protein, n = 168, 77% expression and 45% overexpression	5High: Thyroid, lung, gallbladder, ovary, placenta. Medium: Broadly expressed	ADC: Zt/g4- MMAE (hAb from murine mAb conjugated to MMAE)	Xenograft regression	[49,50]
MUC1, Mucin-1	SPT1MP, extracellular or secreted. Adhesion, protective layer, progression, genotoxic stress response	Protein, n = 52, 94%	5High: Lung, gallbladder, GI tract, female tissues. Medium and low: Adrenal gland, bone marrow and immune, kidney, bladder, male tissues, skin	ADC: mAb-MMAE	PDX regression	[51,52]
CDCP1,CUB domain-containing protein 1	SPMP. Anchorage, migration, proliferation, differentiation	Protein, n = 100, 57%	5Medium and low: Broadly expressed	Ib: Glyco-conjugated palladium complex (Pd-Oqn)	Decreased metastasis	[53-56]
PIM1, Serine/threonine-protein kinase pim-1	Isoform 2: Cell surface, serine/threonine kinase. Proto-oncogene. Survival, proliferation, apoptosis	mRNA, n = 123, increased relative to BC, n = 647	5Low: Broadly expressed	Ib: AZD1208, PIM kinase inhibitors	Stopped PDX growth; increased MYC expression; MYC-driven GEMM	[57-59]
NECTIN4, Nectin-4	SPT1MP. Cell adhesion	mRNA, n = 1175, 61%. Protein, n = 61, 62%; NB, n = 2, 0%; ON, n = 30, 0%	5Medium: Tonsil, oral mucosa, esophagus, bladder, breast, placenta, skin. Low: Pancreas, kidney, female and male tissues	ADC: hAb-MMAE	Rapid, complete, durable responses in PDXs	[60]
GPR55, G-protein coupled receptor 55	MPMP, LPI receptor	Protein, n = 27, 82%	6Broadly expressed, higher levels in bone marrow and immune system, lung, gall bladder, GI tract, bladder, female and male tissues. 772 organs, leukocyte, brain, bone	shRNA against GPR55	Decreased xenograft growth	[61]
LRP8, Low-density lipoprotein receptor-related protein 8	SPT1MP, reelin and apolipoprotein E receptor	mRNA, METABRIC data set, increased relative to BC	5High: Testis. Low: Placenta	siRNA against LRP8; shRNA against LRP8: Inducible	Knockdown in cells. Decreased tumorigenesis via Wnt signaling inhibition	[62,63]

¹MPMP: Multi-pass membrane protein; PMP: Peripheral membrane protein; SPMP: Single-pass membrane protein; SPT1MP: Single-pass type I membrane protein.

²mRNA: Microarray, protein, immunohistochemistry; n: Number of patient specimens; ND: Not determined; NB: Normal breast tissue; BC: Non-TNBC breast cancers; ON: Other normal tissues.

³Ib: Small molecule inhibitor; Ab: Antibody; hAb: Human/humanized; mAb: Monoclonal; CAR-T: CAR-T cells; TLipo: Targeted liposomes; shRNA: Short hairpin RNA; siRNA: Small inhibitory RNA; ADC: Antibody-drug conjugate; MMAE: Monomethyl auristatin E.

⁴CAM: Chick chorioallantoic membrane assay; xenograft: Human TNBC cell lines grown as tumors in immunocompromised mice in vivo; PDX: Patient derived xenografts using TNBC tumor or metastasis specimens; GEMM: Genetically engineered mouse model.

⁵Human Protein Atlas: Protein expression.

⁶Human Protein Atlas: mRNA expression.

⁷UniProt: mRNA expression.

Table 2 Clinical studies targeting the TNBC cell surface

Gene, Protein	Protein type and function1	Expression in TNBC2	Normal tissue expression	Targeted Drug3	Clinical trials	Ref.
EGFR, Epidermal growth factor receptor	(1) SPT1MP, tyrosine kinase receptor; (2) EGF ligands; (3) RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCγ-PKC and STAT pathways	(1) Protein, n = 316, 37%. (2) Protein, n = 930, 54%. (3) Protein, n = 17, 89%	4High: Placenta. Low: Bladder, liver, skeletal muscle, skin, testis, tonsil, vagina	Ib: Afatinib, Gefitinib, Lapatinib. Ab: Cetuximab, MM 151 Ab mixture	Phase 2	[64-71]
VGFR1-3, Vascular endothelial growth factor receptors 1-3	(1) SPT1MP, tyrosine kinase receptors; (2) VEGF A,B,C,D,PGF ligands; (3) Angiogenesis, lymphangiogenesis, cell survival, migration, chemotaxis, invasion, vascular development and permeability	(1) Genomic, increased copy n = 87, 62%; (2) Genomic, increased copy, n = 35, 29%	6VEGF1: 220 organs- lung, placenta, liver, kidney, heart, brain. VEGF2: 208 organs, lung, cornea, broadly expressed. VEGF3: 121 organs– liver, muscle, thymus, placenta, lung, testis, ovary, prostate, heart, kidney	Ib: Cediranib, Apatinib, Lucitanib	Phase 2	[72-74]
FGFR1, Fibroblast growth factor receptor 1	(1) SPT1MP, tyrosine kinase receptor; (2) FGF ligands; (3) Proliferation, migration	Genomic, increased copy, n = 76, 9%; mRNA, n = 56, 4%	4High: Gallbladder, esophagus, fallopian tube, placenta. Medium and Low: Broadly expressed	Ib: Lucitanib	Phase 2	[75-78]
GPNMB, Transmembrane glycoprotein NMB	(1) SPT1MP; (2) Possible melanogenic enzyme	mRNA, n = 103, 29%	5High: Skin. Medium: Cervix, uterine, gallbladder. Low: Broadly expressed	ADC: Glembatumumab vedotin (CDX-011)	Phase 2	[79]
TACSTD2, Tumor-asscociated calcium signal transducer 2 (Trop-2 receptor)	(1) SPT1MP; (2) Possible growth factor receptor	Protein, n = 96, 75%	4Medium: Nasopharynx, bronchus, oral mucosa, esophagus, bladder, seminal vesicle, cervix, uterine, skin. Low: Multiple sites	ADC: Sacituzumab govitecan (IMMU-132)	Phase 2	[21]
SLC39A6, Zinc transporter ZIP6 (LIV-1)	(1) MPMP; (2) Possible zinc-influx transporter	Protein, n = 20, 65%	4High: Adrenal gland, endometrium. Medium and low: Broadly expressed	ADC: SGN–Ab and human Ab-MMAE	Phase 1/2	[22,24]
CD274, Programmed cell death 1 ligand 1 (PD-L1)	(1) SPT1MP; (2) Immune tolerance, antitumor immunity	Protein, n = 127, 30.7%	4High: Lung, placenta. Medium: Lymph node, tonsil, spleen. Low: Appendix, colon	Ab: Avelumab, Atezolizumab, BMS-936559, Durvalumab, HLX20, LDP, LY3300054. CAR-T. CSR-T	Phase 1, 2, 3	[80-85]

¹MPMP: Multi-pass membrane protein; SPMP: Single-pass membrane protein; SPT1MP: Single-pass type I membrane protein.

²mRNA: Microarray, protein, immunohistochemistry; n: Number of patient specimens.

³Ib: Small molecule inhibitor; Ab: Inhibitory monoclonal antibody; ADC: Antibody-drug conjugate; hAb: Humanized antibody; CAR-T: CAR-T cells; CSR-T: Chimeric switch receptor modified T cells.

⁴Human Protein Atlas: Protein expression.

⁵Human Protein Atlas: mRNA expression.

⁶UniProt: mRNA expression.