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.