PRKX, TTBK2 and RSK4 expression causes sunitinib resistance in kidney carcinoma‐ and melanoma‐cell lines

Abstract

Resistance to chemotherapeutic agents constitutes a major problem in the treatment of cancer. Over the past years, multitargeted 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molecular genetic events involved in this processes is pivotal to counteract are not directly targeted by Sunitinib (unpublished data).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.In recent years, kinase inhibitors such as Sunitinib and Sorafenib have been evaluated in clinical trials for their therapeutic efficacy against multiple cancer indications. Both of these cancer drugs are ATP-competitive small molecule kinase inhibitors that have been approved by the Food and Drug Administration for the treatment of metastatic renal cell carcinoma (mRCC). In addition, Sunitinib is approved for the treatment of Gleevec-resistant gastrointestinal stromal tumors (GIST) 1,2 and pancreatic neuroendocrine tumors. It targets and thereby inhibits several receptor tyrosine kinases (RTKs) such as the platelet-derived growth factor receptor beta (PDGFR-b) and the vascular endothelial growth factor receptors 2 and 3 (VEGFR-2 and 3). [3][4][5] Competitive inhibition of these RTKs by Sunitinib is thought to downregulate critical hallmarks of cancer 6 resulting in growth inhibition, prevention of invasivity and induction of apoptosis of cancer cells. 7 These functions are important for the progression of mRCC and GIST, and because of their broad spectrum of kinase inhibitory activity appear to be relevant for the maintenance and progression of many other tumors. 8,9 Consequently, clinical trials, including single-or combinatorial therapy, with Sunitinib for a variety of cancer indications are ongoing. 10 Such efforts include the evaluation of efficacy of Sunitinib in the treatment of melanoma.Sun...

RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer

“…RSK4 has previously been characterized as essential for p53-dependent proliferation arrest as well as stress-and oncogene-induced senescence (28,58,59). Interestingly, the RSK4 isoform exhibits constitutively high activity, is upregulated in MMTV-Myc mouse breast tumors, is aberrantly expressed in breast cancer, and has been implicated in sunitinib resistance (58,(60)(61)(62)(63). Here, we demonstrate that RSK3 and RSK4 can also mediate resistance to PI3K inhibitors in breast cancer cells both in vitro and in vivo.…”

Dual modulation of MCL-1 and mTOR determines the response to sunitinib

“…Tolerated doses of sunitinib therefore inactivate GSK3β and activate ERK, while higher doses activate GSK3β and inhibit ERK. Activation or inhibition of either and MCL-1 to sunitinib resistance with another experimental approach, we examined melanoma cell lines desensitized to sunitinib by continuous exposure to 20 μM sunitinib that was freshly added to the culture medium every 3 days for 12 weeks (42). As shown in Supplemental Figure 8, sunitinib-desensitized cells exhibit higher levels of MCL-1 and mTOR activity as compared with parental cells, further demonstrating the relevance of these newly identified axes in the acquired resistance to sunitinib.…”

Fibroblast Growth Factor Receptor-Dependent and -Independent Paracrine Signaling by Sunitinib-Resistant Renal Cell Carcinoma

“…Sunitinib was originally designed to inhibit cells expressing platelet-derived growth factor receptors (PDGFRs) and VEGFRs (32); however, data concerning the cell types inhibited by sunitinib in kidney cancer remain controversial (35)(36)(37). This controversy results from a lack of appropriate experimental systems.…”

“…Thus, in addition to obstructing EC function and neovascularization, sunitinib also directly inhibits tumor cells dependent on these receptors. However, in contrast to other tumor types, kinases are rarely mutated in ccRCC (34), and whether sunitinib directly affects ccRCC cell growth is unclear (35)(36)(37).…”