PRKX, TTBK2 and RSK4 expression causes Sunitinib resistance in kidney carcinoma- and melanoma-cell lines.
Resistance to chemotherapeutic agents constitutes a major problem in the treatment of cancer. Over the past years, multi-targeted protein kinase inhibitors such as Gleevec, Sunitinib and Sorafenib are gaining wider acceptance for cancer treatment. These drugs show anti-tumor activity in vitro and in patients. Extended usage of these drugs in therapy commonly results in disease progression due to formation of resistance caused by rearrangements and accumulation of mutations in the unstable cancer cell genome. However, the underlying drug-specific mechanisms for the development of resistance remain elusive. Hence, a detailed understanding of the molecular genetic events involved in this processes is pivotal to counteract are not directly targeted by Sunitinib (unpublished data). Therefore, development of specific or multi-targeted inhibitors for these kinases for combinatorial therapy with e.g., an IL-8 neutralizing antibody might circumvent or substantially delay Sunitinib resistance formation and enhance survival prognosis. PRKX, TTBK2 and RSK4 expression. The specific reduction of these genes employing siRNA was sufficient to sensitize the kidney- and melanoma-cell lines against Sunitinib. In line with the elevated expression of PRKX, TTBK2 or RSK4, this sensitization effect was strikingly higher in the Sunitinib resistant cell lines, suggesting an expression-based mechanism of these genes to trigger Sunitinib resistance. Hence, we propose that PRKX, TTBK2 and RSK4 are potential resistance markers in Sunitinib therapy and might therefore represent targets for the development of novel strategies to overcome resistance.
Department of Molecular Biology, Max-Planck-Institute, Martinsried, Germany.
Claus
C
Bender
Axel
A
Ullrich
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics* / Q000378:metabolism; D000077210:Sunitinib
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D034741:RNA, Small Interfering; C109450:PRKX protein, human; C095903:tau-tubulin kinase; D017346:Protein Serine-Threonine Kinases; C501305:RPS6KA6 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D000077210:Sunitinib