Targeting metabolism: A potential strategy for hematological cancer therapy

Table 1 Summary of signaling pathways of hematological cancers

Signaling pathway	Biomarkers	Clinical roles as biomarkers	Ref.
Hypoxia signaling	HIF-1α	Hypoxia strongly correlated clinically to B cell lymphoma and AML proliferation, progression and drug resistance by avoiding oxidative glycolysis but not aerobic glycolysis	[56,57]
Ras/Raf/MAPK	P42/P44 MAPK, P38, P300	Gain-of-function mutation of Kras or Braf (like other kinases) in the tumor cells raise significant resistance to cancer therapy	[58,59]
PI3K-AKT/Ras-ERK/mTOR	Ras-ERK	Mutations affecting kinase activity residues of BRAF (Ras family) and MAPK (ERK family) are correlated to cancer severity, associated to upregulation of these genes in cancer patients as well as increased resistance to conventional chemotherapy; increase of immune checkpoint inhibitors on cancer cells also decreases efficiency of targeted immunotherapy	[60,61]
	mTOR	mTOR constitutive activation is usually found in leukemia patients, which contributes to chemoresistance, disease progression, and unfavorable prognosis	[36-41]
	PI3K-AKT	PTEN, a negative regulator in the PI3K-AKT signaling, becomes inactivated during tumor progression, which deviates the normal signaling and leads to over-reactivation in cancer cells	[62-66]
RTK	Meks/MKKs/ERKs	Mutations that affect RTK signaling often lead to cellular cancerous transformation, and exhibit very limited access to anti-cancer therapy targets	[67,68]
	VEGFR and EGFR	VEGF/VEGFR expression is upregulated in several types of hematolymphoid tumors. It is likely that patients with AML may benefit from EGFR inhibition therapy	[69-76]
NF-κB	NF-κB	NF-κB activity not only promotes tumor cell proliferation, suppresses apoptosis, and attracts angiogenesis but also induces epithelial mesenchymal transition, which facilitates distant metastasis; additionally, it is hardly druggable for specific targeted therapy	[77-80]

Different cellular signaling pathways triggering hematological tumorigenesis, and clinical implications as biomarkers or druggable targets is presented. AML: Acute myeloid leukemia; EGFR: Epidermal growth factor receptor; HIF: Hypoxia-inducible factor; mTOR: Mammalian target of rapamycin; RTK: Receptor tyrosine kinase; NF-κB: Nuclear factor-kappaB; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.