CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought
Open accessAbstract
CDK4/6 inhibitors are among a new generation of therapeutics. Building upon the striking success of the combination of CDK4/6 inhibitors and the hormone receptor antagonist letrozole in breast cancer, many other combinations have recently entered clinical trials in multiple diseases. To achieve maximal benefit with CDK4/6 inhibitors it will be critical to understand the cellular mechanisms by which they act. Here we highlight the mechanisms by which CDK4/6 inhibitors can exert their anti-tumor activities beyond simply enforcing cytostatic growth arrest, and discuss how this knowledge may inform new combinations, improve outcomes, and modify dosing schedules in the future.
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- Premisecitation
In vitro, abemaciclib and ribociclib are more potent against CDK4 than CDK6.
“In vitro studies using cyclin D1/CDK4 and various cyclin D/CDK6 kinases determined that both abemaciclib and ribociclib are more potent against CDK4 than CDK6 (Gelbert et al., 2014; Tripathy et al., 2017) (Table 1).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationnone given
CDK4/6 inhibitors can produce anti-tumor effects that go beyond merely causing cytostatic growth arrest.
“Here we highlight the mechanisms by which CDK4/6 inhibitors can exert their anti-tumor activities beyond simply enforcing cytostatic growth arrest”
Quote in the paperNot a substantial claim- Rests on an assumption: The mechanisms of CDK4/6 inhibitor action observed in preclinical models are relevant to their clinical effects in human cancers.
- Premisecitation
Pan-CDK inhibitors had limited clinical success, partly because dose-limiting toxicities restricted their use.
“Such pan-CDK inhibitors had limited success, due in part to the dose limiting toxicities that hampered their use (Asghar et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Asghar et al., 2015 source
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- Premisecitation
CDK4/6 activity connects extracellular signaling pathways to the cell cycle.
“CDK4/6 activity bridges numerous extracellular signaling pathways to the cell cycle (Sherr and Roberts, 1999).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sherr and Roberts, 1999 source
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- Premisecitation
Palbociclib was the first CDK4/6 inhibitor to show clinical efficacy.
“Although palbociclib was the first CDK4/6 inhibitor to demonstrate clinical efficacy (Finn et al., 2016), there are two others that soon followed.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Finn et al., 2016 source
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- Interpretationcitation
Ribociclib may reach higher cerebrospinal fluid concentrations than palbociclib and abemaciclib, based on mouse models.
“This may translate to higher cerebrospinal fluid concentrations for ribocliclib compared to palbociclib and abemaciclib as noted in mouse models (DiPippo et al., 2016; Raub et al., 2015; Yin et al., 2017).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Rb suppresses growth largely, though not entirely, by binding E2F and repressing transcription at target promoters.
“The growth suppressive properties of Rb are largely, but not completely, associated with its binding to the transcription factor E2F and repressing transcription at target promoters (Classon and Harlow, 2002; Harbour and Dean, 2000; Stevaux and Dyson, 2002).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Abemaciclib has modest activity against CDK9, CDK2, and CDK5 relative to its CDK4 activity.
“In such assays, abemaciclib also has modest activity, relative to its CDK4 inhibitory activity, against cyclin T1/CDK9, cyclin E2/CDK2, p25/CDK5 and p35/CDK5 (Gelbert et al., 2014) (Table 2).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gelbert et al., 2014 source
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- Premisecitation
CDK4/6 kinases can phosphorylate non-Rb targets involved in differentiation, apoptosis, and mitochondrial activity.
“CDK4/6 kinases can phosphorylate factors involved in cell differentiation affecting their transcriptional activity, apoptotic factors affecting their activity, and other factors that can directly affect mitochondrial activity (Hydbring et al., 2016; Lim and Kaldis, 2013).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Hydbring et al., 2016 source
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- cites Lim and Kaldis, 2013
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- Premisecitation
In nearly all human cancer cells, the CDK4/6-Rb circuit is dysregulated by cyclin D1 overexpression, p16 loss, CDK4 mutation to an Ink4-refractory state, or Rb loss.
“In virtually all human cancer cells, this circuit is dysregulated by either overexpression of cyclin D1, loss of p16Ink4a, the mutation of CDK4 to an Ink4-refractory state, or the loss of Rb itself (Classon and Harlow, 2002).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Classon and Harlow, 2002 source
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- Interpretationreasoning
The strong selectivity of all three drugs for Rb-positive over Rb-negative tumor cells suggests that differences in their in vitro kinase profiles may not contribute much to their in vivo activity.
“However, the remarkable specificity of all of these drugs to inhibit the proliferation of Rb-positive tumor cells but not Rb-negative tumor cells, suggests that differences in the in vitro profiles might not contribute that much to their in vivo activity.”
Quote in the paperSubstantial claim - Premisecitation
Palbociclib has similar potency against cyclin D1/CDK4 and cyclin D2/CDK6.
“Palbociclib on the other hand has similar potency when comparing its activity on cyclin D1/CDK4 and cyclin D2/CDK6 (Fry et al., 2004).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fry et al., 2004 source
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- Premisecitation
In normal cells, Rb phosphorylation is typically sequential, first by CDK4 or CDK6 with D-type cyclin, then by cyclin E/CDK2.
“In normal cells, the phosphorylation of Rb is typically carried out by the sequential actions of the CDK4 or CDK6 kinases in complex with a positive regulatory D-type cyclin subunit, followed by cyclin E/CDK2 complexes (Harbour et al., 1999; Lundberg and Weinberg, 1998).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Harbour et al., 1999 source
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- cites Lundberg and Weinberg, 1998
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- Interpretationreasoning
Changing dosing schedules so that cells first exit the cell cycle and are then treated with a second drug targeting signaling events may provide therapeutic gain by minimizing dose and toxicity.
“changing dosing schedules where cells are first induced to exit the cell cycle and are then treated with a second drug targeting such signaling events may even provide a therapeutic gain by minimizing the dose necessary and the subsequent toxicity associated with such inhibitors.”
Quote in the paperSubstantial claim - Premisecitation
Down-regulation of MDM2, redistribution of ATRX, and repression of HRAS transcription are necessary for the transition from CDK4 inhibitor-induced quiescence to senescence in several mesenchymal and epithelial tumor cell lines.
“Specifically, down-regulation of MDM2, redistribution of the chromatin remodeling enzyme ATRX, and repression of HRAS transcription are necessary for the transition of CDK4 inhibitor-induced quiescence into senescence in a number of mesenchymal and epithelial cell lines derived from different tumor types, including breast, non-small cell lung cancer, soft tissue sarcoma and glioma (Kovatcheva et a”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationnone given
Outcomes of CDK4/6 inhibition can depend on whether tumor cells undergo reversible quiescence or more stable senescence.
“Outcomes can depend on the nature of the cytostatic effect in tumor cells, vis a vis whether it undergoes a reversible quiescence or a more stable senescence.”
Quote in the paperNot a substantial claim - Premisecitation
In a few human patients receiving abemaciclib, central nervous system drug levels of 2.2-14.7 nmol/L were achieved.
“In the few human patients receiving abemaciclib, in which drug levels in the central nervous system were measured, accumulations in the range of 2.2–14.7 nmol/L were achieved (Patnaik et al., 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Patnaik et al., 2016 source
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- Interpretationreasoning
Cooperation between CDK4/6 inhibitors and signaling pathway inhibitors may affect sequential decisions in tumor cells.
“Collectively, these studies suggest that the cooperation of CDK4/6 inhibitors and signaling pathway inhibitors may be affecting sequential decisions in the tumor cell.”
Quote in the paperSubstantial claim- Rests on an assumption: The mechanisms of CDK4/6 inhibitor action observed in preclinical models are relevant to their clinical effects in human cancers.
- Interpretationcitation
Increased therapeutic efficiency can occur by enforcing a more durable cell cycle exit.
“Thus, increased therapeutic efficiency can occur by enforcing a more durable cell cycle exit (Figure 1A) as has been extensively reviewed (for example(Sherr et al., 2016)).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sherr et al., 2016 source
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- Interpretationreasoning
Interrupted dosing of CDK4/6 inhibitors can create an opportunity for synergy with combination therapies that interfere with other cell cycle effects.
“When considering the cytostatic effect of CDK4/6 inhibitors, interrupted dosing can provide an opportunity for potent synergy with combination therapies dedicated to interfering with other cell cycle effects.”
Quote in the paperSubstantial claim - Premisecitation
The SASP can create a pro-tumorigenic environment.
“On the other hand, the SASP can create a pro-tumorigenic environment (Coppe et al., 2010; Krtolica et al., 2001; Ruhland et al., 2016).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
CDK4/6 inhibition may elicit senescence through alternative CDK4/6 substrates in addition to cell cycle exit.
“In addition to creating a permissive senescence environment by fulfilling the requisite of cell cycle exit, CDK4/6 inhibition may elicit senescence via alternative CDK4/6 substrates.”
Quote in the paperSubstantial claim - Premisereasoning
FOXM1 suppression after CDK4/6 inhibition leads to reactive oxygen species accumulation and senescence in transformed melanomas but not normal melanocytes.
“FOXM1 suppression following CDK4/6 inhibition leads to the accumulation of reactive oxygen species and senescence in transformed melanomas, but not in normal melanocytes.”
Quote in the paperSubstantial claim - Interpretationcitation
Inhibitors with minimal effect in cycling tumor cells may have more impact in non-cycling CDK4/6 inhibitor-treated cells, potentially pushing them into senescence.
“Inhibitors that have minimal effect in cycling tumor cells may have more of an impact in non-cycling CDK4/6 inhibitor treated cells, perhaps pushing them into senescence.”
Quote in the paperSubstantial claim - Premisecitation
Grade 3-4 neutropenia occurs in about 60% of patients taking palbociclib or ribociclib.
“Grade 3–4 neutropenia is observed in approximately 60% of patients taking palbociclib and ribociclib (Asghar et al., 2015; Hortobagyi et al., 2016).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Depending on cell type and transforming event, some Rb-positive cells undergo quiescence and others senescence after CDK4/6 inhibitor treatment.
“Depending on the cell type and the transforming event, some Rb-positive cells undergo quiescence and others undergo senescence when treated with CDK4/6 inhibitors (Baughn et al., 2006; Choi et al., 2012; Kovatcheva et al., 2015; Michaud et al., 2010; Puyol et al., 2010).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
In some models, resistance to signaling pathway inhibitors can be overcome by adding CDK4/6 inhibitors.
“In some of these models, resistance can be overcome by including CDK4/6 inhibitors in the treatment (Finn et al., 2009; Goel et al., 2016; Kwong et al., 2012; Vora et al., 2014; Zhou et al., 2017).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
In cell lines and xenografts, resistance to signaling pathway inhibitors against estrogen, RAF, EGFR, PI3K, and others is sometimes associated with p16 mutations, upregulated D-type cyclins, or upregulated CDK4/6.
“In cell lines and xenografts, intrinsic and acquired resistance to signaling pathway inhibitors against estrogen, RAF, EGFR, PI3K, and others is sometimes associated with mutations in p16Ink4a, upregulated expression of cyclin D1 or other D-type cyclins, or upregulation of CDK4 or CDK6 (Jiang et al., 2016; Long et al., 2014; Yadav et al., 2014).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Senescent cells express the SASP, a cell-type and signal-specific program of gene expression and cytokine secretion that can sculpt the immune response.
“Senescent cells express a cell type and signal specific program of gene expression and cytokine secretion (the SASP), which can sculpt the immune response (Ohtani et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ohtani et al., 2012 source
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- Interpretationcitation
Interrupted dosing may allow use of DNA-damaging and other cell cycle-targeting therapies because cells become somewhat synchronized upon release and more susceptible.
“interrupted dosing may provide an additional opportunity to use cytotoxic DNA damaging and other cell cycle targeting therapies as the cells become somewhat synchronized upon release, resulting in increased susceptibility to those compounds (Francis et al., 2017; Huang et al., 2012; Yang et al., 2015).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationnone given
Recent investigations offer an alternative mechanistic explanation for the clinical activity of CDK4/6 inhibitors combined with other drugs.
“However, a number of recent investigations provide an alternative mechanistic explanation for the clinical activity of CDK4/6 inhibitors in combination with other drugs.”
Quote in the paperSubstantial claim- Rests on an assumption: The mechanisms of CDK4/6 inhibitor action observed in preclinical models are relevant to their clinical effects in human cancers.
- Premisecitation
In several breast cancer models, including patient-derived xenografts and an MMTV-HER2 mouse, abemaciclib or palbociclib causes growth arrest and increased antigen processing and presentation in tumor cells.
“Recently, in a variety of breast cancer models, including patient-derived xenografts and an MMTV-HER2 mouse, it was demonstrated that abemaciclib or palbociclib induces growth arrest and up-regulation of antigen processing and presentation in the tumor cells (Goel et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Goel et al., 2017 source
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- Premisecitation
BCL2 inhibitors can directly eliminate senescent cells.
“Evidence that BCL2 inhibitors can directly eliminate senescent cells (Chang et al., 2016; Yosef et al., 2016) suggests that combining this with other cancer therapies in a sequential manner might be useful.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
CDK4 is required for proliferation of tumor cells in an RCAS-PDGF/nestin-TvA mouse model of oligodendroglioma.
“The importance of CDK4 activity within the microenvironment was first demonstrated by crossing an RCAS-PDGF/nestin-TvA mouse model of oligodendroglioma into a CDK4 deficient background (Ciznadija et al., 2011). CDK4 is required for the proliferation of the tumor cells; however, reconstituting incipient CDK4 deficient tumor cells with CDK4 expression vectors is not sufficient for tumors to progress”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ciznadija et al., 2011 source
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- Premisecitation
The enhancement of T-cell infiltration by CDK4/6 inhibition is driven at least partly by CDK6-induced phosphorylation of NFAT4.
“This enhancement is driven at least in part by CDK6-induced phosphorylation of NFAT4.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Deng et al., 2017 source
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- Premisecitation
Reconstituting incipient CDK4-deficient tumor cells with CDK4 expression vectors is not sufficient for tumors to progress to a more aggressive state when the rest of the animal is CDK4 deficient.
“CDK4 is required for the proliferation of the tumor cells; however, reconstituting incipient CDK4 deficient tumor cells with CDK4 expression vectors is not sufficient for tumors to progress to a more aggressive state when the rest of the animal is CDK4 deficient.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ciznadija et al., 2011 source
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- Premisecitation
The cyclin D3/CDK6 kinase complex can phosphorylate 6-phosphofructokinase and pyruvate kinase M2.
“The cyclin D3/CDK6 kinase complex can phosphorylate 6-phosphofructokinase and pyruvate kinase M2 (Wang et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wang et al., 2017 source
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- Premisecitation
The lack of progression in this model is associated with defective maturation of tumor-associated microglia, which remain in a sentinel mode in the absence of CDK4.
“The lack of progression in this model is associated with a defect in the maturation of tumor-associated microglia, which remain in a sentinel mode in the absence of CDK4.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ciznadija et al., 2011 source
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- Premisecitation
Animals with CDK4 deficiency, with or without tumors, have lower numbers of infiltrating and circulating CD4+FOXP3+ regulatory T cells, while other T-cell subsets are largely unaffected.
“In both tumor bearing and non-tumor bearing animals, CDK4 deficiency is associated with a reduced number of infiltrating and circulating CD4+FOXP3+ Treg cells with minimal impact on other T-cell subsets (Chow et al., 2010; Goel et al., 2017).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Inhibition of CDK4/6 with any of the three drugs in pancreatic ductal adenocarcinoma cell lines alters glycolytic and oxidative metabolism, increasing ROS in an Rb-dependent manner.
“Inhibition of CDK4/6 with any of the three drugs in pancreatic ductal adenocarcinoma cell lines alters glycolytic and oxidative metabolism leading to an increase in ROS in an Rb-dependent manner (Franco et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Franco et al., 2016 source
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- Interpretationreasoning
By increasing tumor cell antigenicity and suppressing negative regulatory cells, CDK4/6 inhibitors can produce a substantial effect on tumor growth.
“Thus, by enhancing the antigenicity of the tumor cell and suppressing the negative regulatory cells, one can achieve a substantial effect on tumor growth using CDK4/6 inhibitors (Figure 1D).”
Quote in the paperSubstantial claim - Premisecitation
In a mouse model of triple-negative breast cancer, CDK4/6 inhibitors and PI3K inhibitors each have little effect when used alone.
“For example, although individually CDK4/6 inhibitors and PI3K inhibitors have little effect in a mouse model of triple negative breast cancer,”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Teo et al., 2017 source
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- Interpretationcitation
The effect of CDK4/6 inhibitors on the tumor microenvironment may not be solely through blocking Rb phosphorylation and promoting cell cycle exit.
“Interestingly, the action of CDK4/6 inhibitors on the microenvironment might not be only through its ability to block Rb phosphorylation and promote cell cycle exit.”
Quote in the paperSubstantial claim - Premisecitation
CDK4 phosphorylates SPOP, an adaptor for a cullin 3 E3 ubiquitin ligase that binds PD-L1.
“CDK4 was shown to have kinase activity towards SPOP, a cullin 3 E3 ubiquitin ligase adaptor protein that can interact with PD-L1 (Zhang et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhang et al., 2018 source
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- Interpretationcitation
The up-regulation of antigen processing and presentation enhances tumor cell immunogenicity.
“This enhances the immunogenicity of the tumor cells.”
Quote in the paperSubstantial claim - Premisecitation
CDK4 activity is needed for generating CD4+FOXP3+ regulatory T cells capable of inhibiting cytotoxic T-lymphocyte responses.
“Additionally, CDK4 is necessary for the development of CD4+FOXP3+ Treg cells that can suppress CTL responses.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Phosphorylation of AMPKα2 by CDK4 is associated with increased glycolysis and decreased fatty acid oxidation in MEFS.
“For example, phosphorylation of AMPKα2 by CDK4 is associated with increased glycolysis and decreased fatty acid oxidation in MEFS (Lopez-Mejia et al., 2017).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lopez-Mejia et al., 2017 source
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- Premisecitation
Maturation of microglia from sentinel to reactive supports progression of oligodendroglioma into its more aggressive form.
“This is consistent with findings that the maturation of microglia from sentinel to reactive supports the progression of oligodendroglioma into its more aggressive form (Ghosh and Chaudhuri, 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ghosh and Chaudhuri, 2010
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- Premisecitation
The SASP can induce cellular plasticity.
“Furthermore, the SASP can induce cellular plasticity (Ritschka et al., 2017), and cancer cells that manage to escape senescence have a more aggressive, cancer stem cell-like identity (Milanovic et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ritschka et al., 2017 source
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- Interpretationreasoning
CDK4/6 inhibition can profoundly affect tumor growth by acting on tumor microenvironment cells, through effects on proliferation and maturation or on antigen processing and other immunological features of tumor and normal cells.
“These examples illustrate the profound effect that CDK4/6 inhibition can have on tumor growth by acting on the cells of the tumor microenvironment, either by affecting proliferation and maturation, or by affecting antigen processing and other immunological features of the cells, both tumor and normal.”
Quote in the paperSubstantial claim - Premisecitation
Combined treatment with a MEK inhibitor uniquely drove pancreatic ductal adenocarcinoma cells into senescence.
“Interestingly, combined treatment with a MEK inhibitor uniquely drove these cells into senescence.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Franco et al., 2016 source
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- Premisecitation
Cancer cells that escape senescence acquire a more aggressive, cancer stem cell-like identity.
“Furthermore, the SASP can induce cellular plasticity (Ritschka et al., 2017), and cancer cells that manage to escape senescence have a more aggressive, cancer stem cell-like identity (Milanovic et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Milanovic et al., 2018 source
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- Premisecitation
In T-cell acute lymphoblastic leukemia, inhibition of CDK6 or genetic repression of cyclin D3 induces apoptosis.
“In T-cell acute lymphoblastic leukemia (T-ALL), inhibition of CDK6 or genetic repression of cyclin D3 induces apoptosis (Choi et al., 2012; Sawai et al., 2012).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
In mouse xenograft models of colon adenocarcinoma, adding PD-1 blockade to palbociclib improved tumor regression and overall survival.
“Combining palbociclib with a PD-1 blockade enhanced tumor regression and improved overall survival in mouse xenograft models of colon adenocarcinoma (Deng et al., 2017; Zhang et al., 2018).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
When immune checkpoint blockade is added to the CDK4/6 and PI3K inhibitor combination, established tumors undergo complete and durable regression.
“While these investigators did not experimentally address why the combination was better, they further showed that adding an immune checkpoint blockade induces complete and durable regression of established tumors.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Teo et al., 2017 source
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- Interpretationreasoning
CDK4/6 inhibitors slow cancer progression through a wider range of mechanisms than was initially believed.
“It is clear that the mechanisms by which CDK4/6 inhibitors can retard cancer progression are far more diverse than originally thought.”
Quote in the paperSubstantial claim - Interpretationreasoning
Targets of CDK4/6 inhibitors in both tumor cells and the tumor microenvironment can work together to produce the best clinical outcomes.
“Regardless, multiple cellular targets of the CDK4/6 inhibitors, in the tumor cell and in the tumor microenvironment, can also cooperate to yield optimal clinical success.”
Quote in the paperSubstantial claim - Interpretationreasoning
In vivo, CDK4/6 inhibition probably does more than just cause reversible growth arrest.
“The in vivo functions of CDK4/6 inhibition are likely to extend beyond simply enforcing reversible cytostasis.”
Quote in the paperSubstantial claim
- May combine two claims. 28
- Classified as probably not a substantial claim. 5
May combine two claims.
Premisenone givenRibociclib achieves high maximum plasma concentrations exceeding 2 μg/ml and has a half-life greater than 30 hours.
“Ribociclib is notable for achieving high maximum plasma concentrations (exceeding 2 µg/ml) with a long half-life (greater than 30 hours).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAll three CDK4/6 inhibitors are orally available but differ in pharmacokinetics and clinical toxicities, requiring different dosing strategies.
“All three CDK4/6 inhibitors are orally available, but each has differing pharmacokinetics and clinical toxicities (Table 1), necessitating different dosing strategies.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Table 1
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Premisenone givenIn normal and many transformed tumor cells, commitment to the mitotic cycle occurs in G1 and requires phosphorylation and inactivation of Rb.
“Both non-immortal non-transformed cells (hereafter referred to as ‘normal’ cells) and many transformed tumor cells commit irreversibly to the mitotic cell cycle in the G1 phase. Commitment depends on the phosphorylation and inactivation of the retinoblastoma tumor suppressor protein, Rb.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationQuiescent CDK4/6 inhibitor-arrested liposarcoma cells are pushed into senescence by HRAS knockdown, and near-physiologic HRAS mRNA expression prevents senescence after CDK4/6 inhibition while cells still exit the cell cycle.
“Indeed, quiescent CDK4/6 inhibitor arrested liposarcoma tumor cells are pushed into senescence upon knocking down HRAS, and enforced expression of near physiologic levels of HRAS mRNA is able to prevent cells from undergoing senescence following treatment with CDK4/6 inhibitors albeit they still exit the cell cycle (Kovatcheva 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kovatcheva 2017 source
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InterpretationreasoningThe choice between quiescence and senescence may be an important consideration when deciding between abemaciclib and palbociclib/ribociclib because of their differing dosing schedules.
“This outcome may be an important consideration when deciding whether to treat with abemaciclib or palbociclib/ribociclib, given their differing dosing schedules.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationAbemaciclib is better tolerated overall, with 55% of patients having significant adverse events versus 70-80% for ribociclib and palbociclib, and only 21% having grade 3-4 neutropenia.
“Abemaciclib appears to be better tolerated overall, with only 55% of patients experiencing significant adverse events (as compared to 70–80% with ribociclib and palbociclib) and only 21% with grade 3–4 neutropenia.”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationThe SASP can recruit immune cells that mediate tumor clearance or promote paracrine senescence.
“On one hand, the SASP can induce the recruitment of immune cells that will mediate tumor clearance (Xue et al., 2007), or promote paracrine senescence (Acosta et al., 2013; Acosta et al., 2008).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationAbout 10% of patients treated with abemaciclib develop grade 3 diarrhea, which is very rare with the other two inhibitors.
“However, 10% of the patients treated with abemaciclib develop grade 3 diarrhea, which is very rare with the other two inhibitors (Asghar et al., 2015; Hortobagyi et al., 2016).”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationmTOR can toggle the decision between quiescence and senescence.
“It has also been suggested that the mammalian target of rapamycin (mTOR) can toggle the decision between quiescence and senescence (Korotchkina et al., 2010; Leontieva et al., 2012).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisereasoningBecause of significant myelotoxicity, palbociclib and ribociclib require dose interruption and are given on a three-weeks-on/one-week-off schedule to allow marrow recovery.
“Due to the significant myelotoxicity of palbociclib and ribociclib, both drugs require dose-interruption and are administered on a three-weeks-on / one-week-off schedule to allow marrow recovery.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningKnockdown of FOXM1 does not fully reproduce the senescence caused by CDK4/6 inhibition, suggesting that CDK4/6 inhibitors have additional functions beyond FOXM1 suppression.
“Nevertheless, knockdown of FOXM1 does not completely recapitulate the senescence effect of CDK4/6 inhibition, suggesting CDK4/6 inhibitors have functions in addition to suppression of FOXM1.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationmTOR inhibition is crucial for oncogene-induced senescence in mouse melanoma models, and mTOR inhibition can cooperate with CDK4/6 inhibition to drive senescence in melanoma cell lines.
“In contrast to this however, mTOR inhibition is crucial to reach oncogene induced senescence in mouse models of melanoma, and mTOR inhibition can cooperate with CDK4/6 inhibition to drive senescence in melanoma cell lines (Damsky et al., 2015; Yoshida et al., 2016).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationUnlike quiescent cells, senescent cells do not re-enter the cell cycle after removal of the inducing signal and are generally refractory to other proliferation-inducing signals.
“Unlike quiescent cells, senescent cells will not return to the cell cycle following removal of the inducing signal and are generally refractory to other proliferation-inducing signals (Rodier and Campisi, 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rodier and Campisi, 2011 source
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PremisecitationCDK4/6 inhibition leads to loss of multi-site phosphorylation and destabilization of FOXM1.
“CDK4/6 inhibition leads to the loss of multi-site phosphorylation and the destabilization of the transcription factor Forkhead Box M1 (FOXM1) (Anders et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Anders et al., 2011 source
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Premisenone givenCDK4/6 inhibition can alter cellular metabolism, deplete antioxidants, increase reactive oxygen species, and trigger apoptosis.
“CDK4/6 inhibition can also alter cellular metabolism, depleting antioxidants, increasing reactive oxygen species (ROS) and triggering apoptosis.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningAll three inhibitors target the proliferative function of cyclin D-associated kinases in Rb-positive tumor cells to induce cell cycle exit and are largely inactive in Rb-negative cells.
“In summary, all three inhibitors target the proliferative function of the cyclin D associated kinases in Rb positive tumor cells to induce cell cycle exit and they are largely inactive in Rb negative cells.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationRodent models indicate strong efflux of palbociclib from the central nervous system and less efflux of abemaciclib.
“Other rodent models indicate a strong efflux of palbociclib out of the central nervous system, and less so for abemaciclib (Raub et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Raub et al., 2015 source
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May combine two claims.
Premisenone givenCDK4/6 inhibition can affect maturation of sentinel immune cells and expansion of regulatory T-cells.
“CDK4/6 inhibition can also affect both the maturation of sentinel cells of the immune system and the expansion of regulatory T-cells.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationT-ALL cells express very low levels of cyclin D1, cyclin D2, and CDK4, and their proliferative decision depends on cyclin D3 and CDK6.
“These cells express very low levels of cyclin D1, cyclin D2, and CDK4, and the proliferative decision is dependent upon cyclin D3 and CDK6 (Wang et al., 2017; Wolowiec et al., 1996).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationCDK4 phosphorylation of GCN5 can lead to PGC-1α acetylation and is associated with decreased glucose metabolism in hepatic cells.
“In contrast, CDK4 phosphorylation of GCN5 can lead to acetylation of PGC-1α and is associated with decreased glucose metabolism in hepatic cells (Lee et al., 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lee et al., 2014 source
Not checked in the free run.
May combine two claims.
PremisecitationCombining CDK4/6 inhibition with an mTOR inhibitor, a BCL2 inhibitor, or reducing ROS scavengers drives pancreatic ductal adenocarcinoma cells into apoptosis, whereas single agents alone are insufficient.
“Combining CDK4/6 inhibition with an mTOR inhibitor, a BCL2 inhibitor, or reducing the ROS scavengers drives these cells into apoptosis, whereas treatment with single agents alone is not sufficient.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Franco et al., 2016 source
Not checked in the free run.
May combine two claims.
InterpretationcitationCDK4 is required for both tumor cell proliferation and maturation of the tumor microenvironment, and both are necessary for disease progression in this model.
“Thus, CDK4 is required for both the proliferation of tumor cells and for the maturation of the tumor microenvironment, and both are necessary for the progression of disease in this model.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationPersistent senescent cells may contribute to detrimental short- and long-term side effects of treatment, as well as to metastases and relapse.
“Indeed, persistent senescent cells may contribute to detrimental short and long-term side effects of treatment, as well as to metastases and relapse (Demaria et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Demaria et al., 2017 source
Not checked in the free run.
May combine two claims.
PremisecitationTreatment raises the count of CD3+ cells that enter the tumor mass, enabling cytotoxic T-cell stimulation.
“Consistent with this, the number of CD3+ cells recruited into the tumor mass increases after treatment, allowing for the stimulation of cytotoxic T-cells (CTLs).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Goel et al., 2017 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningChanges in metabolism after CDK4/6 inhibition are likely context-specific and may depend on oncogenic drivers that set up unique metabolic pathways and vulnerabilities.
“It is likely that the changes in metabolism after CDK4/6 inhibition will be context-specific and may be dependent on the oncogenic drivers that set up unique metabolic pathways and vulnerabilities.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenThe tumor microenvironment can drive the transition of slow-growing, indolent tumors into a more aggressive state.
“The extraordinarily complex microenvironment is not only supportive for growth but can also drive the transition of slow growing, indolent tumors into a more aggressive state.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThis phosphorylation pushes glycolytic intermediates into the pentose phosphate and serine pathways, and CDK6 inhibition depletes NADPH and glutathione, increasing ROS and apoptosis.
“This has the effect of pushing glycolytic intermediates into the pentose phosphate and serine pathways, and inhibition of CDK6 (through treatment with palbociclib, ribociclib, or knockdown of CDK6) depletes the antioxidants NADPH and glutathione, increasing ROS and apoptosis.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wang et al., 2017 source
Not checked in the free run.
May combine two claims.
PremisecitationIn vitro, blocking CDK4/6 activates T cells that express PD-1 and increases T-cell infiltration.
“CDK4/6 inhibition is also able to stimulate PD-1 expressing T-cells in vitro and enhance T cell infiltration (Deng et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Deng et al., 2017 source
Not checked in the free run.
May combine two claims.
PremisecitationCombined CDK4/6 and PI3K inhibition raises HLA antigen levels, which is accompanied by increased tumor infiltration by cytotoxic CD4+ and CD8+ T cells and natural killer cells and reduced CD4+FOXP3+ regulatory T cells.
“the combination of CDK4/6 and PI3K inhibitors increases the expression of HLA antigens leading to an increase in tumor-infiltrating cytotoxic CD4+ and CD8+ T cells and natural killer cells, and a decrease in the CD4+FOXP3+ Treg suppressor cells (Teo et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Teo et al., 2017 source
Not checked in the free run.
May combine two claims.
PremisecitationPalbociclib treatment inhibits SPOP phosphorylation, promotes SPOP degradation, and blocks proteasome-mediated degradation of PD-L1.
“Treatment with palbociclib inhibits SPOP phosphorylation, promoting its degradation and blocking PD-L1 proteasome mediated degradation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhang et al., 2018 source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningThe most effective way to harness the senescence-promoting effects of CDK4/6 inhibitors may be to first induce senescence and then eliminate persistent senescent cells.
“Collectively, these observations suggest that the most effective approach to harness the senescence promoting effects of CDK4/6 inhibitors may be to first induce senescence and then eliminate the persistent senescent cells.”
Quote in the paperNot a substantial claim- Rests on an assumption: The senescence and SASP programs induced by CDK4/6 inhibitors in model systems are representative of those in human tumors.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationcitationCombining BCL2 inhibitors with other cancer therapies in a sequential manner might be useful.
“Evidence that BCL2 inhibitors can directly eliminate senescent cells (Chang et al., 2016; Yosef et al., 2016) suggests that combining this with other cancer therapies in a sequential manner might be useful.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn an oligodendroglioma model, PDGF overexpression can start disease in tumor cells with CDK4, but CDK4 deficiency in the microenvironment prevents low-grade lesions from becoming high-grade lethal malignancies.
“In the oligodendroglioma model described above (Ciznadija et al., 2011), ectopic PDGF expression is sufficient to drive the initiation of disease in CDK4 positive tumor cells, but if the microenvironment is CDK4 deficient these low-grade lesions would not progress to high grade lethal malignancies.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ciznadija et al., 2011 source
Not checked in the free run.
The paper relies on this without support.
The mechanisms of CDK4/6 inhibitor action observed in preclinical models are relevant to their clinical effects in human cancers.
“Here we highlight the mechanisms by which CDK4/6 inhibitors can exert their anti-tumor activities beyond simply enforcing cytostatic growth arrest and discuss how this knowledge may inform new combinations, improve outcomes and modify dosing schedules in the future.”
The paper relies on this without support.
The senescence and SASP programs induced by CDK4/6 inhibitors in model systems are representative of those in human tumors.
“Collectively, these observations suggest that the most effective approach to harness the senescence promoting effects of CDK4/6 inhibitors may be to first induce senescence and then eliminate the persistent senescent cells.”
The paper relies on this without support.
Rb-negative tumors do not respond significantly to CDK4/6 inhibitors.
“Given the importance of CDK4 in the tumor microenvironment, it may be somewhat surprising that CDK4/6 inhibitors have no significant effect on Rb-negative tumors.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CDK4/CDK6 inhibitors and other CDK inhibitors both halt malignant cell proliferation and produce multiple immunomodulatory effects.
“Accumulating evidence suggests that CDK4/CDK6 inhibitors, as well as inhibitors of other CDKs, do not only arrest the proliferation of malignant cells, they also mediate multipronged immunomodulatory effects (Klein et al., 2018; Petroni et al., 2020)”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Klein et al., 2018
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- Authors
- Klein, M. E., Kovatcheva, M., Davis, L. E., Tap, W. D., & Koff, A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Oregon Health & Science University (US)
- Corresponding author
- Koff, Andrew
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 34
- Issue
- 1
- Pages
- 9-20
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC6039233
- OpenAlex
- W2799372852
- Cited by
- 378
- References
- 70
- Citations by year
- 2026: 22 · 2025: 50 · 2024: 63 · 2023: 46 · 2022: 37 · 2021: 58 · 2020: 55 · 2019: 31 · 2018: 16
- FWCI
- 7.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P30 CA008748, CA140146)
- Sarcoma Foundation of America
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- CDK4/6 inhibitors, cyclin-dependent kinases, mechanism of action, breast cancer, letrozole, combination therapy, anticancer activity, dosing regimen
- MeSH terms
- Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Humans, Neoplasms, Drug Design, Signal Transduction, Cellular Senescence, Protein Kinase Inhibitors, Cell Proliferation, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Molecular Targeted Therapy, Cell Cycle Checkpoints
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
Statistics and arithmetic are recomputed, not judged.
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