Table 1.

Comparison of Acquired (Evasive) and Intrinsic (Preexisting) Therapy Resistance

			Mechanism of Developing		Drugs Known to be
	Underlying Process	Involved Cells	Resistance	End Result	Affected	References
Acquired (evasive) resistance	Angiogenic switch	Vascular cells	Multiple proangiogenic and antiangiogenic molecules act to promote new vessel growth.	RCC progression	Sorafenib, sunitinib, axitinib, pazopanib, tivozanib	49-55
	Increased pericyte coverage of tumor vessels	Perivascular cells/vascular smooth muscle cells	The abnormal development of vasculature is stabilized, leading to tumorigenesis.	Excessive angiogenesis of RCC; more aggressive tumor type	Sorafenib, sunitinib, axitinib, pazopanib, tivozanib	34, 35, 44, 56
	Recruitment of proangiogenic inflammatory cells from bone marrow	Vascular progenitor cells; proangiogenic monocytes; VEGFR-1⁺ hemangiocytes; CD11b⁺ myeloid cells	Bone marrow–derived cells accumulate inside and around the tumor. New blood vessels supply the developing tumor.	RCC adaptation to hypoxia conditions; tumorigenesis	Sorafenib, sunitinib, axitinib, pazopanib, tivozanib	57-62
	Lysosomal sequestration of drugs	ccRCC cells	Sunitinib is captured and stored in intracellular compartments (other than in ccRCC cells) instead of reaching cancer cells.	Low concentrations of sunitinib in plasma and serum and in ccRCC cells; therapeutic concentrations not achieved	Sunitinib only	46, 63-65
	Epithelial to mesenchymal transition	Healthy epithelial cells	Polarized epithelial cells convert into motile epithelial cells or to cells with stem cell–like properties.	Escape of cells from their biological structure; tumorigenesis; acquired resistance	Sorafenib, sunitinib, axitinib, pazopanib, tivozanib	6, 66-68
Intrinsic (preexisting) resistance	Insufficient inhibition of the targets by the treatment		Lesser concentration of the drug is unable to fully inhibit the targets. The uninhibited targets are still active and drive the underlying mechanisms.	Tumor cells proliferate despite therapy; increased tumor invasiveness	Sorafenib, sunitinib, axitinib, pazopanib, tivozanib	47-49
	Immunomodulatory effects	MDSCs	MDSCs are present in the blood, lymph nodes, and bone marrow of patients with cancer and inhibit NK cells, adaptive T cells, and macrophages. They simultaneously stimulate regulatory T cells. MDSCs may stimulate tumor growth.	Tumor growth; tumor sustainability; maintenance of nutrient supply to the tumor	Sunitinib, but potentially all drugs	50
	Reduced apoptosis	Extrinsic and intrinsic apoptosis proteins; cell surface death receptors	Both extrinsic and intrinsic mechanisms of apoptosis are reduced in RCC, yet no defined underlying mechanism has been established.	Unregulated tumor growth; increased invasiveness; increased resistance to the targeted drugs	Potentially all available drugs unless specifically targeting the apoptotic pathways	51

ccRCC, clear cell renal cell carcinoma; MDSCs, myeloid-derived suppressor cells; NK, natural killer; RCC, renal cell carcinoma; VEGFR, vascular endothelial growth factor receptor.