Table 2.

Metabolic inhibitors in combination with targeted therapy for cancer therapy.

Targeted Metabolism	Metabolic Inhibitor	Cell Signalling Pathway Inhibitor	Preclinical Data	Clinical Data
OXPHOS	Phenformin	BRAF inhibition (Dabrafenib + Trametinib)	Melanoma [5,234]	Phase I—Melanoma (NCT03026517)
	VLX600 (mitochondrial inhibitor)	cKIT inhibition (Imatinib)	GIST [235]
	IACS-010759 (complex I inhibitor)	Ibrutinib	MCL [48]
	Metformin	BRAF TKI (vemurafenib or dabrafenib + trametinib)		Phase I/II—Melanoma (NCT01638676) Phase I/II—Melanoma (NCT02143050)
		EGFR TKI (erlotinib, afatinib or gefitinib)		Phase II—NSCLC (NCT03071705) [236]
	OPB compounds (OPB-51602, OPB-1110077)	EGFR TKI Cell signalling pathway inhibitors		Phase I—NSCLC (NCT01184807) [193] Phase IIa—Oncogene-addicted cancers (NCT03158324)
Glycolysis	3PO	Nintedanib, sunitinib	Breast [237]
	PFK158 (PFKFB3 inhibitor)	Vemurafenib	Melanoma [238]
	PFK15 (PFKFB3 inhibitor)	Rapamycin	AML [239]
	2-DG	Afatinib	NSCLC [240]
	2-DG HK2 silencing	Sorafenib	HCC [230,241]
Glutaminolysis	GLS inhibition (BPTES, CB-839)	BRAF TKI	Melanoma [50]
		Osimertinib		Phase I/II—NSCLC (NCT03831932)
		Erlotinib		Phase I—NSCLC (NCT02071862)
		Palbociclib		Phase I/II—Solid tumours (NCT03965845)
		Cabozantinib	Multiple: melanoma, glioma, NSCLC, sarcoma, PDAC, prostate [242]	Phase I—RCC (NCT02071862) [243] Phase II—RCC (CANTATA: NCT03428217)
Metabolic inhibition + mTOR Pathway inhibition	Compound 968	Rapamycin	GBM [244]
	CB-839	Everolimus		Phase Ib—RCC (NCT02071862) Phase II—RCC (ENTRATA: NCT03163667)
	Metformin	Rapamycin	Pancreatic [245]
		Everolimus	Breast [246,247]	Phase Ib—Solid tumours [248]
		Temsirolimus		Phase I—advanced/refractory cancers (NCT01529593), solid tumours or lymphoma (NCT00659568) [249]
		Sapanisertib (TAK-228) mTOR1/2 inhibitor		Phase I—solid tumours (NCT03017833)