The protein kinase C (PKC) inhibitors combined with chemotherapy in the treatment of advanced non-small cell lung cancer: meta-analysis of randomized controlled trials

Zhang, L. L.; Cao, Feifei; Wang, Yingmei; Meng, Fanqiao; Zhang, Y.; Zhong, Diansheng; Zhou, Qinghua

doi:10.1007/s12094-014-1241-3

Cited by 36 publications

(31 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Three decades later, it became apparent that not only were they not working as anti-cancer drugs, but in some cases, PKC inhibitors were worsening patient outcome. Most striking, a meta-analysis of five clinical trials for non-small cell lung carcinomas revealed worsened patient outcome when PKC inhibitors (enzastaurin, an ATP competitive inhibitor, or aprinocarsen, a PKCα antisense oligonucleotide) were combined with chemotherapy compared with chemotherapy alone (Zhang et al 2015). Thus, clinical trials unveiled a disconnect between the biology of phorbol esters and the presumed function of PKC.…”

Section: Pkc and Cancermentioning

confidence: 99%

Protein kinase C: perfectly balanced

Newton

2018

Critical Reviews in Biochemistry and Molecular Biology

227

216

View full text Add to dashboard Cite

Protein kinase C (PKC) isozymes belong to a family of Ser/Thr kinases whose activity is governed by reversible release of an autoinhibitory pseudosubstrate. For conventional and novel isozymes, this is effected by binding the lipid second messenger, diacylglycerol, but for atypical PKC isozymes, this is effected by binding protein scaffolds. PKC shot into the limelight following the discovery in the 1980s that the diacylglycerol-sensitive isozymes are ‘receptors’ for the potent tumor-promoting phorbol esters. This set in place a concept that PKC isozymes are oncoproteins. Yet three decades of cancer clinical trials targeting PKC with inhibitors failed and, in some cases, worsened patient outcome. Emerging evidence from cancer-associated mutations and protein expression levels provide a reason: protein kinase C isozymes generally function as tumor suppressors and their activity should be restored, not inhibited, in cancer therapies. And whereas not enough activity is associated with cancer, variants with enhanced activity are associated with degenerative diseases such as Alzheimer’s disease. This review describes the tightly controlled mechanisms that ensure PKC activity is perfectly balanced and what happens when these controls are deregulated. PKC isozymes serve as a paradigm for the wisdom of Confucius: “to go beyond is as wrong as to fall short.”

show abstract

Section: Pkc and Cancermentioning

confidence: 99%

Protein kinase C: perfectly balanced

Newton

2018

Critical Reviews in Biochemistry and Molecular Biology

227

216

View full text Add to dashboard Cite

show abstract

“…However, these efforts were largely unsuccessful. Indeed, a meta analysis of five clinical trials for non-small cell lung carcinoma revealed that patient outcome worsened when PKC inhibitors were combined with chemotherapy compared to chemotherapy alone [12]. Why the disconnect?…”

Section: Phorbol Estersmentioning

confidence: 99%

Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor

Newton

Brognard

2017

Trends in Pharmacological Sciences

View full text Add to dashboard Cite

The discovery in the 1980s that protein kinase C (PKC) is a receptor for the tumor-promoting phorbol esters fueled the dogma that PKC is an oncoprotein. Yet 30+ years of clinical trials for cancer using PKC inhibitors not only failed, but in some instances worsened patient outcome. The recent analysis of cancer-associated mutations, from diverse cancers and throughout the PKC family, revealed that PKC isozymes are generally inactivated in cancer, supporting a tumor suppressive function. In keeping with a bona fide tumor suppressive role, germ line causal loss of function (LOF) mutations in one isozyme have recently been identified in lymphoproliferative disorders. Thus, strategies in cancer treatment should focus on restoring, rather than inhibiting, PKC.

show abstract

“…Based on the dogma that PKC isozymes contribute positively to cancer progression, many PKC inhibitors have entered clinical trials; however, they have been ineffective (Mackay and Twelves, 2007). In fact, a recent meta-analysis of controlled trials of PKC inhibitors combined with chemotherapy versus chemotherapy alone revealed that PKC inhibitors significantly decreased response rates and disease control rates in non-small cell lung cancer (Zhang et al, 2014). Why has inhibiting PKC failed in the clinic?…”

Section: Introductionmentioning

confidence: 99%

Cancer-Associated Protein Kinase C Mutations Reveal Kinase’s Role as Tumor Suppressor

Antal

Hudson

Kang

et al. 2015

Cell

292

275

View full text Add to dashboard Cite

SUMMARY Protein kinase C (PKC) isozymes have remained elusive cancer targets despite the unambiguous tumor promoting function of their potent ligands, phorbol esters, and the prevalence of their mutations. We analyzed 8% of PKC mutations identified in human cancers and found that, surprisingly, most were loss of function and none were activating. Loss-of-function mutations occurred in all PKC subgroups and impeded second-messenger binding, phosphorylation, or catalysis. Correction of a loss-of-function PKCβ mutation by CRISPR-mediated genome editing in a patient-derived colon cancer cell line suppressed anchorage-independent growth and reduced tumor growth in a xenograft model. Hemizygous deletion promoted anchorage-independent growth, revealing that PKCβ is haploinsufficient for tumor suppression. Several mutations were dominant negative, suppressing global PKC signaling output, and bioinformatic analysis suggested that PKC mutations cooperate with co-occurring mutations in cancer drivers. These data establish that PKC isozymes generally function as tumor suppressors, indicating that therapies should focus on restoring, not inhibiting, PKC activity.

show abstract

The protein kinase C (PKC) inhibitors combined with chemotherapy in the treatment of advanced non-small cell lung cancer: meta-analysis of randomized controlled trials

Abstract: The use of PKC inhibitors in addition to chemotherapy was not a valid alternative for patients with advanced NSCLC.

Cited by 36 publications

References 31 publications

Protein kinase C: perfectly balanced

Protein kinase C: perfectly balanced

Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor

Cancer-Associated Protein Kinase C Mutations Reveal Kinase’s Role as Tumor Suppressor

Contact Info

Product

Resources

About