Table 1.

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

Mechanism of DevelopingDrugs Known to be
Underlying ProcessInvolved CellsResistanceEnd ResultAffectedReferences
Acquired (evasive) resistanceAngiogenic switchVascular cellsMultiple proangiogenic and antiangiogenic molecules act to promote new vessel growth.RCC progressionSorafenib, sunitinib, axitinib, pazopanib, tivozanib49-55
Increased pericyte coverage of tumor vesselsPerivascular cells/vascular smooth muscle cellsThe abnormal development of vasculature is stabilized, leading to tumorigenesis.Excessive angiogenesis of RCC; more aggressive tumor typeSorafenib, sunitinib, axitinib, pazopanib, tivozanib34, 35, 44, 56
Recruitment of proangiogenic inflammatory cells from bone marrowVascular progenitor cells; proangiogenic monocytes; VEGFR-1+ hemangiocytes; CD11b+ myeloid cellsBone marrow–derived cells accumulate inside and around the tumor. New blood vessels supply the developing tumor.RCC adaptation to hypoxia conditions; tumorigenesisSorafenib, sunitinib, axitinib, pazopanib, tivozanib57-62
Lysosomal sequestration of drugsccRCC cellsSunitinib 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 achievedSunitinib only46, 63-65
Epithelial to mesenchymal transitionHealthy epithelial cellsPolarized epithelial cells convert into motile epithelial cells or to cells with stem cell–like properties.Escape of cells from their biological structure; tumorigenesis; acquired resistanceSorafenib, sunitinib, axitinib, pazopanib, tivozanib6, 66-68
Intrinsic (preexisting) resistanceInsufficient inhibition of the targets by the treatmentLesser 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 invasivenessSorafenib, sunitinib, axitinib, pazopanib, tivozanib47-49
Immunomodulatory effectsMDSCsMDSCs 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 tumorSunitinib, but potentially all drugs50
Reduced apoptosisExtrinsic and intrinsic apoptosis proteins; cell surface death receptorsBoth 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 drugsPotentially all available drugs unless specifically targeting the apoptotic pathways51
  • ccRCC, clear cell renal cell carcinoma; MDSCs, myeloid-derived suppressor cells; NK, natural killer; RCC, renal cell carcinoma; VEGFR, vascular endothelial growth factor receptor.