Chemoproteomics Reveals Novel Protein and Lipid Kinase Targets of Clinical CDK4/6 Inhibitors in Lung Cancer

Sumi, Natalia J.; Kuenzi, Brent M.; Knezevic, Claire E.; Rix, Lily; Rix, Uwe

doi:10.1021/acschembio.5b00368

Cited by 70 publications

(84 citation statements)

References 31 publications

(74 reference statements)

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“…Consistent with the gene silencing, the dual CAMKK2/AMPK inhibitor compound C did not synergize with paclitaxel. In addition, combination of paclitaxel with the CDK4/6 inhibitor ribociclib, which has no activity against RSK1/2, IGF1R, or FAK1, 37 did not exhibit synergy, whereas the FAK1/RSK/IGF1R inhibitor CEP-37440 38 strongly synergized with paclitaxel (Supplementary Fig. 7e–f).…”

Section: Resultsmentioning

confidence: 98%

Polypharmacology-based ceritinib repurposing using integrated functional proteomics

et al. 2017

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Targeted drugs are effective when directly inhibiting strong disease drivers, but only a small fraction of diseases feature defined actionable drivers. Alternatively, network-based approaches can uncover new therapeutic opportunities. Applying an integrated phenotypic screening, chemical and phosphoproteomics strategy, we here describe the ALK inhibitor ceritinib to have activity across several ALK-negative lung cancer cell lines and identify new targets and network-wide signaling effects. Combining pharmacological inhibitors and RNA interference revealed a polypharmacology mechanism involving the non-canonical targets IGF1R, FAK1 and RSK1/2. Mutating the downstream signaling hub YB1 protected cells from ceritinib. Consistent with YB1 signaling being known to cause taxol resistance, ceritinib combination with paclitaxel displayed strong synergy, particularly in cells expressing high FAK autophosphorylation, which we show to be prevalent in lung cancer. Together, we present a systems chemical biology platform for elucidating multi-kinase inhibitor polypharmacology mechanisms, subsequent design of synergistic drug combinations, and identification of mechanistic biomarker candidates.

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Section: Resultsmentioning

confidence: 98%

Polypharmacology-based ceritinib repurposing using integrated functional proteomics

et al. 2017

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“…In a recent study on lung cancer, palbociclib was shown to interact with several protein and lipid kinases beyond CDK4/6 (23). Based on this report and our unexpected finding in Figure 2A, we performed screening for other potential targets with a commercial antibody array kit.…”

Section: Resultsmentioning

confidence: 99%

Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

Olmez

Brenneman

Xiao

et al. 2017

Clinical Cancer Research

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Purpose Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM. Experimental Design Preclinical in vitro and in vivo assays using primary GBM cell lines were performed. Results We show that the CDK4/6 inhibitor palbociclib suppresses the activity of downstream mediators of the mTOR pathway, leading to rebound mTOR activation that can be blocked by the mTOR inhibitor everolimus. We further show that mTOR inhibition with everolimus leads to activation of the Ras mediator Erk that is reversible with palbociclib. The combined treatment strongly disrupts GBM metabolism, resulting in significant apoptosis. Further increasing the utility of the combination for brain cancers, everolimus significantly increases the brain concentration of palbociclib. Conclusions Our findings demonstrate that the combination of CDK4/6 and mTOR inhibition has therapeutic potential against GBM and suggest it should be evaluated in a clinical trial.

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“…An alternative approach defines the array of biophysical interactions that a drug is capable of making which enables the connection to a wealth of known physiology. Previously, subsets of CDK drugs have been studied (41,(47)(48)(49) with more systematic comparisons occurring by literature reviews (4,9,19). In the current study, a synergistic combination of cellular, biochemical, and crystallographic analysis is used to characterize multiple generations of CDK drugs in a single study.…”

Section: Discussionmentioning

confidence: 99%

“…The kinome interaction assessments (purified proteins, tumor cell lysates) identify CDK9 as a likely candidate that contributes to abemaciclib's clinical pharmacology. It should be noted that another chemoproteomic study came to a different conclusion of about CDK9 selectivity but it used structural analogues of the CDK drugs to capture interacting kinases which could introduce kinase selectivity artifacts (47). Abemaciclib has significant biochemical potency for CDK5 so engagement of the atypical CDKs cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance

Chen

Lee

et al. 2016

Molecular Cancer Therapeutics

325

286

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Therapeutically targeting aberrant intracellular kinase signaling is attractive from a biological perspective but drug development is often hindered by toxicities and inadequate efficacy. Predicting drug behaviors using cellular and animal models is confounded by redundant kinase activities, a lack of unique substrates, and cell-specific signaling networks. Cyclin-dependent kinase (CDK) drugs exemplify this phenomenon because they are reported to target common processes yet have distinct clinical activities. Tumor cell studies of ATP-competitive CDK drugs (dinaciclib, AG-024322, abemaciclib, palbociclib, ribociclib) indicate similar pharmacology while analyses in untransformed cells illuminates significant differences. To resolve this apparent disconnect, drug behaviors are described at the molecular level. Nonkinase binding studies and kinome interaction analysis (recombinant and endogenous kinases) reveal that proteins outside of the CDK family appear to have little role in dinaciclib/palbociclib/ribociclib pharmacology, may contribute for abemaciclib, and confounds AG-024322 analysis. CDK2 and CDK6 cocrystal structures with the drugs identify the molecular interactions responsible for potency and kinase selectivity. Efficient drug binding to the unique hinge architecture of CDKs enables selectivity toward most of the human kinome. Selectivity between CDK family members is achieved through interactions with nonconserved elements of the ATPbinding pocket. Integrating clinical drug exposures into the analysis predicts that both palbociclib and ribociclib are CDK4/6 inhibitors, abemaciclib inhibits CDK4/6/9, and dinaciclib is a broad-spectrum CDK inhibitor (CDK2/3/4/6/9). Understanding the molecular components of potency and selectivity also facilitates rational design of future generations of kinase-directed drugs.

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Chemoproteomics Reveals Novel Protein and Lipid Kinase Targets of Clinical CDK4/6 Inhibitors in Lung Cancer

Cited by 70 publications

References 31 publications

Polypharmacology-based ceritinib repurposing using integrated functional proteomics

Polypharmacology-based ceritinib repurposing using integrated functional proteomics

Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance

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