The DOI matches its Crossref record; 70 of the 70 references it cites were found in a registry or an index; none of the 92 sources its claims cite is checked for support yet.
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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In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 INHIBITORS: A TRIO OF COMPOUNDS WITH DISTINCT ADVANTAGES
What the sources say
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we highlight the mechanisms by which CDK4/6 inhibitors can exert their anti-tumor activities beyond simply enforcing cytostatic growth arrest”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclear- Rests on an assumption: The mechanisms of CDK4/6 inhibitor action observed in preclinical models are relevant to their clinical effects in human cancers.
In the paper
“Such pan-CDK inhibitors had limited success, due in part to the dose limiting toxicities that hampered their use (Asghar et al., 2015).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > THE IMPORTANCE OF CYCLIN D-CDK4/6 IN THE CELL CYCLE
What the sources say
- Not checked yetcites Asghar et al., 2015 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“CDK4/6 activity bridges numerous extracellular signaling pathways to the cell cycle (Sherr and Roberts, 1999).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > THE IMPORTANCE OF CYCLIN D-CDK4/6 IN THE CELL CYCLE
What the sources say
- Not checked yetcites Sherr and Roberts, 1999 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Although palbociclib was the first CDK4/6 inhibitor to demonstrate clinical efficacy (Finn et al., 2016), there are two others that soon followed.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 INHIBITORS: A TRIO OF COMPOUNDS WITH DISTINCT ADVANTAGES
What the sources say
- Not checked yetcites Finn et al., 2016 source
Strength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 INHIBITORS: A TRIO OF COMPOUNDS WITH DISTINCT ADVANTAGES
What the sources say
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > THE IMPORTANCE OF CYCLIN D-CDK4/6 IN THE CELL CYCLE
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 INHIBITORS: A TRIO OF COMPOUNDS WITH DISTINCT ADVANTAGES
What the sources say
- Not checked yetcites Gelbert et al., 2014 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > THE IMPORTANCE OF CYCLIN D-CDK4/6 IN THE CELL CYCLE
What the sources say
- Not checked yetcites Hydbring et al., 2016 source
- Not checked yetcites Lim and Kaldis, 2013
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > THE IMPORTANCE OF CYCLIN D-CDK4/6 IN THE CELL CYCLE
What the sources say
- Not checked yetcites Classon and Harlow, 2002 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 28
- Probably not a substantial claim. 5
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Ribociclib is notable for achieving high maximum plasma concentrations (exceeding 2 µg/ml) with a long half-life (greater than 30 hours).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 INHIBITORS: A TRIO OF COMPOUNDS WITH DISTINCT ADVANTAGES
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“All three CDK4/6 inhibitors are orally available, but each has differing pharmacokinetics and clinical toxicities (Table 1), necessitating different dosing strategies.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 INHIBITORS: A TRIO OF COMPOUNDS WITH DISTINCT ADVANTAGES
What the sources say
- Not checked yetcites Table 1
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > THE IMPORTANCE OF CYCLIN D-CDK4/6 IN THE CELL CYCLE
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > SENESCENCE AFTER CDK4/6 INHIBITOR INDUCED GROWTH ARREST
What the sources say
- Not checked yetcites Kovatcheva 2017 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This outcome may be an important consideration when deciding whether to treat with abemaciclib or palbociclib/ribociclib, given their differing dosing schedules.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > SENESCENCE AFTER CDK4/6 INHIBITOR INDUCED GROWTH ARREST
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 INHIBITORS: A TRIO OF COMPOUNDS WITH DISTINCT ADVANTAGES
What the sources say
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > SENESCENCE AFTER CDK4/6 INHIBITOR INDUCED GROWTH ARREST
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 INHIBITORS: A TRIO OF COMPOUNDS WITH DISTINCT ADVANTAGES
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > SENESCENCE AFTER CDK4/6 INHIBITOR INDUCED GROWTH ARREST
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 INHIBITORS: A TRIO OF COMPOUNDS WITH DISTINCT ADVANTAGES
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > SENESCENCE AFTER CDK4/6 INHIBITOR INDUCED GROWTH ARREST
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > SENESCENCE AFTER CDK4/6 INHIBITOR INDUCED GROWTH ARREST
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > SENESCENCE AFTER CDK4/6 INHIBITOR INDUCED GROWTH ARREST
What the sources say
- Not checked yetcites Rodier and Campisi, 2011 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > SENESCENCE AFTER CDK4/6 INHIBITOR INDUCED GROWTH ARREST
What the sources say
- Not checked yetcites Anders et al., 2011 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“CDK4/6 inhibition can also alter cellular metabolism, depleting antioxidants, increasing reactive oxygen species (ROS) and triggering apoptosis.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 INHIBITORS REINFORCE CYTOSTASIS INDUCED BY SIGNALING PATHWAY INHIBITORS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 INHIBITORS: A TRIO OF COMPOUNDS WITH DISTINCT ADVANTAGES
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Other rodent models indicate a strong efflux of palbociclib out of the central nervous system, and less so for abemaciclib (Raub et al., 2015).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 INHIBITORS: A TRIO OF COMPOUNDS WITH DISTINCT ADVANTAGES
What the sources say
- Not checked yetcites Raub et al., 2015 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“CDK4/6 inhibition can also affect both the maturation of sentinel cells of the immune system and the expansion of regulatory T-cells.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 INHIBITORS REINFORCE CYTOSTASIS INDUCED BY SIGNALING PATHWAY INHIBITORS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > THE IMPACT OF CDK4/6 INHIBITORS ON CELLULAR METABOLISM
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > THE IMPACT OF CDK4/6 INHIBITORS ON CELLULAR METABOLISM
What the sources say
- Not checked yetcites Lee et al., 2014 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > THE IMPACT OF CDK4/6 INHIBITORS ON CELLULAR METABOLISM
What the sources say
- Not checked yetcites Franco et al., 2016 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 IN THE TUMOR MICROENVIRONMENT
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > SENESCENCE AFTER CDK4/6 INHIBITOR INDUCED GROWTH ARREST
What the sources say
- Not checked yetcites Demaria et al., 2017 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 IN THE TUMOR MICROENVIRONMENT
What the sources say
- Not checked yetcites Goel et al., 2017 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > THE IMPACT OF CDK4/6 INHIBITORS ON CELLULAR METABOLISM
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 IN THE TUMOR MICROENVIRONMENT
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > THE IMPACT OF CDK4/6 INHIBITORS ON CELLULAR METABOLISM
What the sources say
- Not checked yetcites Wang et al., 2017 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“CDK4/6 inhibition is also able to stimulate PD-1 expressing T-cells in vitro and enhance T cell infiltration (Deng et al., 2017).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 IN THE TUMOR MICROENVIRONMENT
What the sources say
- Not checked yetcites Deng et al., 2017 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 IN THE TUMOR MICROENVIRONMENT
What the sources say
- Not checked yetcites Teo et al., 2017 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Treatment with palbociclib inhibits SPOP phosphorylation, promoting its degradation and blocking PD-L1 proteasome mediated degradation.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 IN THE TUMOR MICROENVIRONMENT
What the sources say
- Not checked yetcites Zhang et al., 2018 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > SENESCENCE AFTER CDK4/6 INHIBITOR INDUCED GROWTH ARREST
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence.
- Rests on an assumption: The senescence and SASP programs induced by CDK4/6 inhibitors in model systems are representative of those in human tumors.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > SENESCENCE AFTER CDK4/6 INHIBITOR INDUCED GROWTH ARREST
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence.
In the paper
“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.”
§ CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought > CDK4/6 IN THE TUMOR MICROENVIRONMENT
What the sources say
- Not checked yetcites Ciznadija et al., 2011 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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?
In the citing paper
“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
Citations
Cites
CDK inhibitors: positive and negative regulators of G1-phase progression
Sherr, C. J., & Roberts, J. M. (1999) · Genes & Development · doi:10.1101/gad.13.12.1501 · Cited by 6,115
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206
Palbociclib and letrozole in advanced breast cancer
Finn, R. S., Martin, M., Rugo, H. S., Jones, S., Im, S.-A., Gelmon, K., Harbeck, N., Lipatov, O. N., Walshe, J. M., Moulder, S., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1607303 · Cited by 3,007
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473
A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2784 · Cited by 2,278 · cited 1×
“, 2007), or promote paracrine senescence (Acosta et al., 2013; Acosta et al., 2008).”
Four faces of cellular senescence
Rodier, F., & Campisi, J. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201009094 · Cited by 2,070 · cited 1×
“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).”
BackgroundRibociclib as first-line therapy for HR-positive, advanced breast cancer
Hortobagyi, G. N., Stemmer, S. M., Burris, H. A., Yap, Y.-S., Sonke, G. S., Paluch-Shimon, S., Campone, M., Blackwell, K. L., André, F., Winer, E. P., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1609709 · Cited by 2,039 · cited 2×
“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).”
BackgroundClearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice
Chang, J., Wang, Y., Shao, L., Laberge, R.-M., Demaria, M., Campisi, J., Janakiraman, K., Sharpless, N. E., Ding, S., Feng, W., et al. (2016) · Nature Medicine · doi:10.1038/nm.4010 · Cited by 1,819
The history and future of targeting cyclin-dependent kinases in cancer therapy
Asghar, U., Witkiewicz, A. K., Turner, N. C., & Knudsen, E. S. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4504 · Cited by 1,767
Krtolica, A., Parrinello, S., Lockett, S., Desprez, P.-Y., & Campisi, J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.211053698 · Cited by 1,730
Flagged first, then by citations
Cited by
Sorted by citations
CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review
Farhood, B., Najafi, M., & Mortezaee, K. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27782 · Cited by 1,701
The broken cycle: E2F dysfunction in cancer
Kent, L. N., & Leone, G. W. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0143-7 · Cited by 807
Targeting cell-cycle machinery in cancer
Suski, J. M., Braun, M., Strmiska, V., & Siciński, P. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.03.010 · Cited by 587
Regulating tumor suppressor genes: post-translational modifications
Chen, L., Liu, S., & Tao, Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0196-9 · Cited by 449
Braal, C. L., Jongbloed, E. M., Wilting, S. M., Mathijssen, R. H. J., Koolen, S. L. W., & Jager, A. (2020) · Drugs · doi:10.1007/s40265-020-01461-2 · Cited by 462
Metadata
- 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 › Oncology › 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.
A language model drew the claims from the paper on 2026-10-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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