The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study

Millward, Michael; House, Colin M.; Bowtell, David D.L.; Webster, Lorraine K.; Olver, Ian; Gore, Martin; Copeman, Michael; Lynch, Kevin; Yap, A.; Wang, Y.; Cohen, Pamela S.; Zalcberg, John

doi:10.1038/sj.bjc.6603331

Cited by 52 publications

(33 citation statements)

References 12 publications

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“…Likewise, another KIT inhibitor, PKC412, showed little activity in melanoma (12). However, Becker et al (36) observed in a recent editorial that their imatinib trial was underpowered to detect activity in the subtypes of melanomas most likely to harbor a KIT mutation.…”

Section: Discussionmentioning

confidence: 99%

KIT Gene Mutations and Copy Number in Melanoma Subtypes

Beadling

Jacobson‐Dunlop

Hodi

et al. 2008

Clinical Cancer Research

606

485

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Purpose:We recently identified a KITexon11mutation in an anorectal melanoma of a patient who had an excellent response to treatment with imatinib.To determine the frequency of KIT mutations across melanoma subtypes, we surveyed a large series of tumors. Experimental Design: One hundred eighty-nine melanomas were screened for mutations in KIT exons 11, 13, and 17. KIT copy number was assessed by quantitative PCR. A subset of cases was evaluated for BRAF and NRAS mutations. Immunohistochemistry was done to assess KIT (CD117) expression. Results: KIT mutations were detected in 23% (3 of 13) of acral melanomas, 15.6% (7 of 45) of mucosal melanomas, 7.7% (1 of 13) of conjunctival melanomas, 1.7% (1 of 58) of cutaneous melanomas, and 0% (0 of 60) of choroidal melanomas. Almost all the KIT mutations were of the type predicted to be imatinib sensitive.There was no overlap with NRAS mutations (11.1% of acral and 24.3% of mucosal tumors) or with BRAF mutations (absent in mucosal tumors). Increased KIT copy number was detected in 27.3% (3 of 11) of acral and 26.3% (10 of 38) of mucosal melanomas, but was less common among cutaneous (6.7%; 3 of 45), conjunctival (7.1%; 1 of 14), and choroidal melanomas (0 of 28). CD117 expression, present in 39% of 105 tumors representing all melanoma types, did not correlate with either KIT mutation status or KIT copy number. Conclusions: Our findings confirm that KIT mutations are most common in acral and mucosal melanomas but do not necessarily correlate with KIT copy number or CD117 expression. Screening for KIT mutations may open up new treatment options for melanoma patients.

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Section: Discussionmentioning

confidence: 99%

KIT Gene Mutations and Copy Number in Melanoma Subtypes

Beadling

Jacobson‐Dunlop

Hodi

et al. 2008

Clinical Cancer Research

606

485

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“…Midostaurin (34) was the first PKC inhibitor evaluated in clinical trials; however, it has failed to demonstrate significant activity in clinical trials to date (35). ISIS 3521, a phosphorothioate antisense oligonucleotide targeting the 3 0 -untranslated region of PKC-a mRNA (36,37), demonstrated anticancer activity in various types of cancers, including tumors refractory to conventional chemotherapy (38,39), but has so far failed to exert clinically significant efficacy when combined with chemotherapy against advanced lung cancer in phase III trials (40).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Protein Kinase C/Twist1 Signaling Augments Anticancer Effects of Androgen Deprivation and Enzalutamide in Prostate Cancer

Shiota

Yokomizo

Takeuchi

et al. 2014

Clinical Cancer Research

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Purpose: The progression of prostate cancer to metastatic and castration-resistant disease represents a critical step. We previously showed that the transcription factor Twist1, which promotes epithelialmesenchymal transition, was involved in castration-resistant progression. Similarly, protein kinase C (PKC) has been implicated in both metastatic progression and castration resistance in prostate cancer.Experimental Design: In this study, we aimed to elucidate the role of PKC/Twist1 signaling in castration resistance, and to apply this information to the development of a novel therapeutic concept using PKC inhibitor Ro31-8220 against prostate cancer using various prostate cancer cell lines.Results: Androgen deprivation and the next-generation antiandrogen enzalutamide induced PKC activation and Twist1 expression, which were reversed by the PKC inhibitor Ro31-8220. Ro31-8220 suppressed cell proliferation in androgen-dependent prostate cancer LNCaP cells, which was augmented by its combination with androgen deprivation or enzalutamide. The favorable anticancer effects of the combination of Ro31-8220 and enzalutamide were also observed in castration-resistant C4-2 and 22Rv1 cells. Furthermore, PKC phosphorylation was elevated in castration-resistant and enzalutamide-resistant cells compared with their parental cells, leading to persistent sensitivity to Ro-31-8220 in castration-and enzalutamide-resistant cells.Conclusions: Taken together, these findings indicate that PKC/Twist1 signaling contributes to castration resistance as well as enzalutamide resistance in prostate cancer, and suggest that therapeutics targeting PKC/ Twist1 signaling, such as PKC inhibitors, represent a promising novel therapeutic strategy for prostate cancer, especially castration-resistant prostate cancer, when combined with enzalutamide. Clin Cancer Res; 20(4); 951-61. Ó2013 AACR.

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“…As mentioned earlier, the BIM PKC412 is a PKC inhibitor, but it has also been identified as an FLT3 inhibitor (40) along with the compound CEP-701 (4). In a phase II trial of PKC412, plasma concentrations of the parent compound as high as 4 Amol/L have been reported (41). Interestingly, serum concentrations of metabolites of PKC412, also indolocarbazoles, have been reported to be as high as 22 Amol/L (41), thus suggesting that the metabolites might also act as inhibitors of ABCG2.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ABCG2-mediated transport by protein kinase inhibitors with a bisindolylmaleimide or indolocarbazole structure

Robey

Shukla

Steadman³

et al. 2007

Molecular Cancer Therapeutics

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ABCG2 is a transporter with potential importance in cancer drug resistance, drug oral absorption, and stem cell biology. In an effort to identify novel inhibitors of ABCG2, we examined the ability of commercially available bisindolylmaleimides (BIM) and indolocarbazole protein kinase inhibitors (PKI) to inhibit ABCG2, given the previous demonstration that the indolocarbazole PKI UCN-01 interacted with the transporter. At a concentration of 10 Mmol/L, all of the compounds tested increased intracellular fluorescence of the ABCG2-specific substrate pheophorbide a in ABCG2-transfected HEK-293 cells by 1.3-to 6-fold as measured by flow cytometry; the ABCG2-specific inhibitor fumitremorgin C increased intracellular fluorescence by 6.6-fold. In 4-day cytotoxicity assays, wild-type ABCG2-transfected cells were not more than 2-fold resistant to any of the compounds, suggesting that the PKIs are not significantly transported by ABCG2. BIMs I, II, III, IV, and V, K252c, and arcyriaflavin A were also able to inhibit [ 125 I]iodoarylazidoprazosin labeling of ABCG2 by 65% to 80% at 20 Mmol/L, compared with a 50% to 70% reduction by 20 Mmol/L fumitremorgin C. K252c and arcyriaflavin A were the most potent compounds, with IC 50 values for inhibition of [ 125 I]iodoarylazidoprazosin labeling of 0.37 and 0.23 Mmol/L, respectively. K252c and arcyriaflavin A did not have any effect on the ATPase activity of ABCG2. Four minimally toxic compounds-BIM IV, BIM V, arcyriaflavin A, and K252c-reduced the relative resistance of ABCG2-transfected cells to SN-38 in cytotoxicity assays. We find that indolocarbazole and BIM PKIs directly interact with the ABCG2 protein and may thus increase oral bioavailability of ABCG2 substrates.

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The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study

Cited by 52 publications

References 12 publications

KIT Gene Mutations and Copy Number in Melanoma Subtypes

KIT Gene Mutations and Copy Number in Melanoma Subtypes

Inhibition of Protein Kinase C/Twist1 Signaling Augments Anticancer Effects of Androgen Deprivation and Enzalutamide in Prostate Cancer

Inhibition of ABCG2-mediated transport by protein kinase inhibitors with a bisindolylmaleimide or indolocarbazole structure

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