Table 1.

Outcome for preclinical trials in non-small cell lung cancer with GSIs as monotherapy or in combination with other chemotherapeutics or targeted agents.

Treatment		Outcome	Reference
GSI	Combination
DAPT	SA	✓Least effective clinical GSI in cleaving NOTCH receptors ✓NOTCH1 gain-of function/loss of function NUMB mutations: sensitive ✓↑ G1/G0 and G2/M arrest ✓↓ ALDH+ cells with ↑ NOTCH 1/2/3, HEY1/2 and HESl ✓EGFR low/wt cells: ↓ proliferation GO/G1 arrest, ↑ Beclin-1 ✓Reverts NOTCH-induced EMT phenotype	(74, 98, 132, 155, 156)
	Cisplatin Paclitaxel Doxorubicin Docetaxel Gefitinib Pterostilbene	✓↑ P-c-Jun, ↑ AP-1-regulated miR-451, ↓ MDR-1 ✓Cisplatin-treated cells with ↑ drug transporters: sensitive ✓↓ Viability of cisplatin-resistant CD133+ cells ✓Gefitinib-resistant cells: ↑ NOTCH1, HES1, and cyclin D1, ↓ P21 WAF1/CIP1 ✓GSI + cisplatin/docetaxel/gefitinib: in vivo chemosensitization, ↑ G2/M arrest, ↓ proliferation, ↑ apoptosis ✓GSI + Pterostilbene: ↓ tumor growth in vivo, ↓ pterostilbene-mediated ↑NICD, HES1 and ↓ PI3K/AKT, cyclin D1, survivin, DNA-PK, P-mTOR, P-S6 ribosomal protein	(87, 98, 130, 157, 158, 159)
MRK-003	SA	✓NOTCH1 gain-of function/loss of NUMB mutations: sensitive ✓↓ Tumor formation in H1299 stem-like cells expressing ↑ NOTCH 2/4, HES1, HEY1 resistant to cisplatin/docetaxel, rescued by N1/2 ICD (not N3 ICD) in sphere formation ✓↓ NOTCH1-mediated ↑ IGFR-1-mediated AKT-1 expression by ↓ PTEN under hypoxia and ↑ apoptosis under hypoxia ✓↓ NOTCH3: ↓ growth and ↑ tumor apoptosis via ↓ p-ERK, p-BCL-2, BCL-Xl and ↑ BIM, BAX, p-BAD proteins	(53, 74, 107, 160)
	Docetaxel Dominant neg. IGFR-1 Erlotinib	✓GSI + docetaxel: ↓↓ tumor growth ✓IGF-1R sensitizes cells to GSI-induced apoptosis ✓GSI + erlotinib: ↑ ERK-regulated ↑ BIM and ↓ tumor growth	(53, 74, 107, 160)
PF-3084014	SA	✓Preferentially ↓ NOTCH2, but also other NOTCH receptors, SPPL2b, APPC100, and APP	(155)
	Erlotinib	✓↓ ALDH+ NOTCH3-dependent cells in EGFR-mutated cell lines ✓EGFR negatively regulates Notch activity via its TK activity	(129)
RO4929079	SA	✓Preferentially ↓ NOTCH1 followed by NOTCH2/3, SPPL2b and APPC100	(155)
	Erlotinib	✓↓ miR-223, CD44+ erlotinib-resistant cells ✓↑ FBXW7 and reverses erlotinib-resistance	(161)
BMS-708163	SA	✓↓ NOTCH1, HES1, PI3K, and AKT (but not mTOR) and Ki67 ✓↑ G1 arrest, active caspase 3 and PARP	(162)
	Gefitinib	✓↓ 3D colony growth, Ki67, gefitinib-resistant tumor xenograft growth ✓↑ Cytotoxicity and apoptosis
LY-685458	SA	✓↓ NOTCH, DLK1-induced ↑ MMP9 expression, invasion	(163)
LY-411575	DDR1 inhibitor 7rh	✓Additive tumor growth delay of KRAS-driven (including TP53-null) PDX NSCLC and ↑ apoptosis ✓Similar therapeutic efficacy to cisplatin/paclitaxel, but displayed coagulative necrosis, ↓ p-AKT and p-p38	(164)
GSI XX	YC-1 HIF inh RT	✓RT-induced HIF-1α ↑ NOTCH3 under hypoxia (reversed by YC-1) ✓GSI XX 24 h post YC-1 + 8 Gy: strongest tumor growth delay in vivo	(165)
GSI?	Cisplatin ABT-737 (BH3-only mimetic)	✓↓ NOTCH3: ↓ the cisplatin-mediated ↑ in spheroid forming efficiencies, LC3 and ↓ ALDHA1, CD44 ✓GSI + ABT-737: synergistic ↓ proliferation, tumor growth in vivo and ↑ BIM and cleaved PARP	(88, 166)

SA, single agent; ↑, increase/upregulated; ↓, decrease/downregulated; GSI, gamma-secretase inhibitor; GSI?, unspecified GSI; RT, radiotherapy; neg., negative; EGFR, epidermal growth factor receptor; IGF-1R, insulin-like growth factor 1 receptor; DDR1, discoidin domain receptor 1; SPPL2b, signal peptide peptidase-like 2b; APPC100, C-terminal 100 amino acids of amyloid precursor protein; APP, amyloid precursor protein; PI3K, Phosphoinositide 3-kinase; PARP, poly ADP-ribose polymerase 1; DLK1, delta-like non-canonical NOTCH ligand 1; MMP9, matrix metallopeptidase 9.