Cancer Cell
 2016
DOI: 10.1016/j.ccell.2016.02.006
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Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors

Shom Goel
1
,
Qi Wang
2
,
April C. Watt
3
et al.

Abstract: Summary Using transgenic mouse models, cell line-based functional studies and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR-family kinases, re-sensitizing tumors to EGFR/HER2 blockade. Consequently, dua… Show more

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Cited by 479 publications

(491 citation statements)
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“…The changes in gene expression were confirmed at the protein level for a number of E2F dependent genes (Figure 2E). Interestingly, despite reports that CDK4/6 inhibition leads to increased phosphorylation of AKT through RB suppression of mTORC2 activation (24, 25), we found no evidence of increased AKT phosphorylation or altered mTOR signalling by palbociclib in our experiments (Figure 2C).…”
Section: Resultscontrasting
confidence: 95%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
“…The changes in gene expression were confirmed at the protein level for a number of E2F dependent genes (Figure 2E). Interestingly, despite reports that CDK4/6 inhibition leads to increased phosphorylation of AKT through RB suppression of mTORC2 activation (24, 25), we found no evidence of increased AKT phosphorylation or altered mTOR signalling by palbociclib in our experiments (Figure 2C).…”
Section: Resultscontrasting
confidence: 95%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
“…While our data indicated that palbociclib may affect multiple pathways including the PI3K/AKT/mTOR signaling pathway (Fig EV3D), the PI3K/AKT/mTOR pathway inhibition was weak and evident only at higher drug concentrations (Fig EV3E–G). These findings are consistent with previous observations that CDK4/6 inhibition can partially attenuate mTORC1 activity (Goel et al , ).…”
Section: Resultssupporting
confidence: 94%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
“…3B ). These observations are in agreement with the already known “senescence-like phenotype” induced by CDK4/6 inhibitors ( 19, 27, 28 ). As for classical senescence, we found that cells treated with palbociclib for 72 hours showed an activation of the SA β-gal ( Fig.…”
Section: Resultssupporting
confidence: 92%
“…A clear senescence-like phenotype was observed at the end of the 72 h treatment in BT474 and MCF7 (as example of HER2+ and HER2 low cells) (Fig 3a ); indeed cells showed altered morphology, flattening and increased cell area (Fig 3b). These observations are in agreement with the already known "senescence-like phenotype" induced by CDK4/6 inhibitors 19,27,28 As for classical senescence, we found that cells treated with Palbociclib for 72 h showed an activation of the Senescence Associated galactosidase (SA -gal) (Figure 3a). However, after Palbociclib removal (3 days WO) cells reverted to the original appearance and the activity of SA -gal decreased.…”
Section: Resultssupporting
confidence: 92%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
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