A phase II study of enzastaurin in combination with erlotinib in patients with previously treated advanced non-small cell lung cancer

Clément-Duchêne, Christelle; Natale, Ronald B.; Jahan, Thierry; Krupitskaya, Yelena; Osarogiagbon, Raymond U.; Sanborn, Rachel E.; Bernstein, Eric; Dudek, Arkadiusz Z.; Latz, Jane E.; Shi, Peipei; Wakelee, Heather A.

doi:10.1016/j.lungcan.2012.06.003

Cited by 12 publications

(7 citation statements)

References 48 publications

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“…However, the therapeutic efficacy of PKC inhibitors in the treatment of cancer patients has been disappointing (34–36). Our results indicate that melanoma cells with GNAQ or GNA11 mutations are selectively sensitive to PKC inhibition, consistent with the findings from other groups (20, 21).…”

Section: Discussionmentioning

confidence: 99%

Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations

et al. 2013

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Uveal melanoma (UM) is a genetically and biologically distinct type of melanoma, and once metastatic there is no effective treatment currently available. 80% of UMs harbor mutations in the Gαq family members GNAQ and GNA11. Understanding the effector pathways downstream of these oncoproteins is important to identify opportunities for targeted therapy. We report consistent activation of the protein kinase C (PKC) and MAPK pathways as a consequence of GNAQ or GNA11 mutation. PKC inhibition with AEB071 or AHT956 suppressed PKC and MAPK signalling and induced G1 arrest selectively in melanoma cell lines carrying GNAQ or GNA11 mutations. In contrast, treatment with two different MEK inhibitors, PD0325901 and MEK162, inhibited the proliferation of melanoma cell lines irrespective of their mutation status, indicating that in the context of GNAQ or GNA11 mutation, MAPK activation can be attributed to activated PKC. AEB071 significantly slowed the growth of tumors in an allograft model of GNAQQ209L transduced melanocytes, but did not induce tumor shrinkage. In vivo and in vitro studies showed that PKC inhibitors alone were unable to induce sustained suppression of MAP-kinase signaling. However, combinations of PKC and MEK inhibition, using either PD0325901 or MEK162, led to sustained MAP-kinase pathway inhibition and showed a strong synergistic effect in halting proliferation and in inducing apoptosis in vitro. Furthermore, combining PKC and MEK inhibition was efficacious in vivo, causing marked tumor regression in a uveal melanoma xenograft model. Our data identifies PKC as a rational therapeutic target for melanoma patients with GNAQ or GNA11 mutations, and demonstrates combined MEK and PKC inhibition is synergistic, with superior efficacy compared to treatment with either approach alone.

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Section: Discussionmentioning

confidence: 99%

Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations

et al. 2013

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“…PKC isozymes, in particular PKCβ, a binding partner of ZMYND8, are important mediators of VEGF signalling, and their inhibition leads to decreased endothelial cell proliferation and a reduction in neovascularization of malignant tumours [29,30]. Although a PKCβ inhibitor, LY317615 (enzastaurin), is undergoing clinical trials for several malignancies [31–34], the high degree of sequence homology and structural similarity of the catalytic regions among PKC isozymes and other protein kinases suggest that development of isozyme‐selective inhibitors will be extremely challenging [35]. In addition, because multiple PKC isozymes are expressed in all cell types throughout the body, which perform crucial roles in normal physiology, systemic inhibition of PKCs may result in undesired on‐target side effects such as delayed wound healing [36].…”

Section: Discussionmentioning

confidence: 99%

Zinc finger MYND‐type containing 8 promotes tumour angiogenesis via induction of vascular endothelial growth factor‐A expression

Kuroyanagi¹,

Zhang²,

Ariyoshi³

et al. 2014

FEBS Letters

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a b s t r a c tZinc finger, MYND-type containing 8 (ZMYND8) encodes a receptor for activated C-kinase protein.Here, we report that ZMYND8 promotes angiogenesis in prostate cancer xenografts in zebrafish, as well as tube formation in human umbilical vascular endothelial cell (HUVEC) cultures. Using transcriptome analyses, we found upregulation of ZMYND8 expression in both zebrafish prostate cancer xenografts and prostate cancer samples from patients. In vitro and in vivo ZMYND8 knockdown suppressed angiogenesis, whereas ZMYND8 overexpression enhanced angiogenesis. Notably, ZMYND8 induced vegfa mRNA expression selectively in prostate cancer xenografts. Integrated analysis of human and zebrafish transcriptomes, which identified ZMYND8, might be a powerful strategy to determine also other molecular targets for inhibiting prostate cancer progression.

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“…A current study that explored the treatment of patients with advanced stage IIIB or IV NSCLC with erlotinib and enzastaurin. Results revealed that while the enzastaurin did not help improve the patient response to chemotherapy, it did not worsen usual results either (Clement-Duchene et al, 2012). Overall, the combination therapy presented to be well tolerated in the NSCLC patients.…”

Section: Combination Therapy To Improve Treatment With Erlotinibmentioning

confidence: 88%

Erlotinib Resistance in Lung Cancer: Current Progress and Future Perspectives

Tang¹,

Salama²,

Gadgeel³

et al. 2013

Front. Pharmacol.

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Lung cancer is the most common cancer in the world. Despite modern advancements in surgeries, chemotherapies, and radiotherapies over the past few years, lung cancer still remains a very difficult disease to treat. This has left the death rate from lung cancer victims largely unchanged throughout the past few decades. A key cause for the high mortality rate is the drug resistance that builds up for patients being currently treated with the chemotherapeutic agents. Although certain chemotherapeutic agents may initially effectively treat lung cancer patients, there is a high probability that there will be a reoccurrence of the cancer after the patient develops resistance to the drug. Erlotinib, the epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor, has been approved for localized as well as metastatic non-small cell lung cancer where it seems to be more effective in patients with EGFR mutations. Resistance to erlotinib is a common observation in clinics and this review details our current knowledge on the subject. We discuss the causes of such resistance as well as innovative research to overcome it. Evidently, new chemotherapy strategies are desperately needed in order to better treat lung cancer patients. Current research is investigating alternative treatment plans to enhance the chemotherapy that is already offered. Better insight into the molecular mechanisms behind combination therapy pathways and even single molecular pathways may help improve the efficacy of the current treatment options.

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A phase II study of enzastaurin in combination with erlotinib in patients with previously treated advanced non-small cell lung cancer

Abstract: In previously treated, unselected, advanced NSCLC patients, the addition of enzastaurin to erlotinib did not improve PFS, response, or OS compared with historical data of single-agent erlotinib, but was well tolerated.

Cited by 12 publications

References 48 publications

Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations

Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations

Zinc finger MYND‐type containing 8 promotes tumour angiogenesis via induction of vascular endothelial growth factor‐A expression

Erlotinib Resistance in Lung Cancer: Current Progress and Future Perspectives

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