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  • Renal cell carcinoma RCC accounts for more

    2023-01-24

    Renal cell carcinoma (RCC) accounts for more than 12,000 cancer deaths in the United States (Jemal et al., 2003). The current treatment includes surgical resection followed by interleukin-2 or Interferon-α treatment. Some patients experience distant metastatic lesions of RCC. In the last 5 years, receptor tyrosine kinases have become prominent anti-tumor targets for cancer therapy development including RCC. Currently, two tyrosine kinase inhibitors namely, sunitinib and sorafenib are approved by FDA for RCC treatment. In addition, there are several clinical trials of different phases for RCC, of which, EGFR, VEGFR and PDGFR inhibitors are being investigated for their potency (Potti and George, 2004). Interestingly, high EGFR protein in RCC has been reported since 1989 (Sargent et al., 1989; Uhlman et al., 1995), however, it is not clear if this is due to overexpression of the receptor or defective receptor downregulation. In this work, we propose that the high EGFR found in A498 RCC is due to ACK1 S985 N that prevents receptor downregulation, resulting in constitutively strong mitogenic signaling in the cells. In addition, despite high EGFR protein level, A498 remained highly resistant to gefitinib treatment. Our mechanistic studies on ACK1 in A498 suggested a regulatory role in EGFR downregulation. Indeed, silencing of ACK1 sensitized cancer alzheimer's disease to gefitinib. A high gefitinib concentration was used in our experiment to accommodate the transient siRNA silencing effect. We expect similar, if not better sensitization, at repeated low dosage treatment of the ACK1-silenced cells. Taken together, these findings open up an opportunity of combinational therapy against ACK1 not only in high EGFR expressing renal tumors, but also in lung cancer where a large percentage of tumors overexpressing EGFR are also resistant to EGFR inhibitors.
    Conclusion We characterized a novel point mutation, S985 N on ACK1's UBA domain. This mutation renders the ACK1's role on EGFR downregulation inefficient which resulted in constitutively high mitogenic signal transduction in the tumor cells. Although the work focuses on ACK1 extended stability and its effect on EGFR degradation, nonetheless, it also provides a probable explanation on how the high ACK1 protein observed in cancer cells could promote tumorigenesis. Currently, we are in the process of collecting and sequencing ACK1 in clinical tumor samples from various tissue types. It would be very exciting to see if we could locate similar mutations in different tumor types that have been associated with high ACK1 expression levels.
    Acknowledgements
    Activated Cdc42-associated kinase (ACK1) is a non-receptor tyrosine kinase originally identified by virtue of its binding to GTP-bound small GTPase Cdc42. It is ubiquitously expressed and is activated by multiple extracellular growth factors such as EGF, PDGF, and TGFβ. Upon activation, ACK1 mediates a signaling cascade by directly interacting with and phosphorylating downstream effectors. Considerable attention has been paid to the biological function of ACK1 in recent years especially to its involvement in cancer. For example, gene amplification and over-expression of ACK1 were found in multiple cancers including lung, ovarian and prostate cancers and were associated with poor prognosis and metastatic phenotypes. Activated ACK1 has been shown to phosphorylate and activate androgen receptor function and to promote the progression of prostate cancer. More recently, activated ACK1 was found to phosphorylate and promote the activation of Akt, a protein kinase that plays a central role in growth, proliferation and cell survival in various cancers. Taken together, these literature data suggest that ACK1 is a potential target for cancer treatment. Moreover, a potent and selective small molecule ACK1 inhibitor will provide a valuable tool to help to further probe the role of ACK1 in cancer. A series of pyrazolo[3,4-]pyrimidines has been previously disclosed as ACK1 inhibitors. Compound is a representative example from this series with a reported ACK1 cellular mechanistic IC value of 20nM (). A series of 5,6-biarylfuro[2,3-]pyrimidines and bioisosteric 2,3-diarylfuro[2,3-]pyridines and 5,6-biarylpyrrolo[2,3-]pyrimidines have also been reported as potent ACK1 inhibitors. For example, compound inhibits ACK1 in a cellular mechanistic assay with an IC value of 10nM. Another compound from this class, AIM-100 (compound , ) moderately inhibits ACK1 with a cellular mechanistic IC value of 0.62μM, suppressing both ACK1 Tyr284- and androgen receptor Tyr267-phosphorylations in vitro., Unfortunately, these disclosed compounds suffered poor oral pharmacokinetic (PK) properties due to metabolic instability which prevented them from being utilized alzheimer further in the in vivo setting. Herein we report our drug discovery effort around small molecule ATP competitive ACK1 inhibitors. More specifically, the initial discovery, optimization and in vitro and in vivo characterization of a series of imidazo[1,5-]pyrazine-derived inhibitors of ACK1 which possessed favorable drug-like properties including potency, selectivity and orally bioavailability.