CDK4/6 Inhibitors Impair Recovery from Cytotoxic Chemotherapy in Pancreatic Adenocarcinoma

Salvador-Barbero, Beatriz; Álvarez-Fernández, Mónica; Zapatero-Solana, Elisabet; Bakkali, Aicha El; Menéndez, Camino; López-Casas, Pedro P.; Domenico, Tomás Di; Xie, Tao; VanArsdale, Todd; Shields, David J.; Hidalgo, Manuel; Malumbres, Marcos

doi:10.1016/j.ccell.2020.09.012

Cited by 59 publications

(62 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S2b) in the PARPi-resistant cell lines. Regarding the relationship between cell cycle arrest and DNA damage, we speculated that CDK4/6i interferes with the cytotoxic effect of DNAdamaging agents, as CDK4/6i arrests cells in G1, thereby protecting the cells from damage during DNA replication or mitosis, which was consistent with some previous studies [34,35]. Under the combined treatment, the antitumor effect of CDK4/6i (inhibiting DNA repair and increasing DNA damage) may partly depend on the pretreatment effect of PARPi.…”

Section: Cdk4/6i Results In Defective G2 Cell Cycle-dependent Dna Repsupporting

confidence: 87%

Efficacy and Mechanism of the Combination of PARP and CDK4/6 Inhibitors in the Treatment of Triple-negative Breast Cancer

Zhu

CHEN

Huang

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients with BRCA mutations and their efficacy is even more limited in triple-negative breast cancer (TNBC) due to clinical primary and acquired resistance. Here, we found that the efficacy of PARPi in TNBC can be improved with CDK4/6 inhibitors (CDK4/6i).Methods: We screened primary PARPi-sensitive and resistant cell lines from existing BRCAmut/TNBC cell lines and generated cells with acquired PARPi resistance by gradually increasing the concentration. The effects of the PARPi olaparib and the CDK4/6i palbociclib on BRCAmut/TNBC cell lines were examined in both sensitive and resistant cells in vitro and in vivo. Pathway and gene alterations were assessed mechanistically and pharmacologically.Results: We demonstrated for the first time that the combination of PARPi and CDK4/6i has synergistic effects against BRCAmut/TNBC both in vitro and in vivo. In the PARPi-sensitive MB436 cells, the single agent olaparib significantly inhibited cell viability and affected cell growth due to severe DNA damage. In the PARPi-resistant HCC1937 and SUM149 cells, single-agent olaparib was ineffective due to potential homologous recombination (HR) repair, and the combination of PARPi and CDK4/6i greatly inhibited HR during the G2 phase, increased DNA damage and inhibited tumor growth. Inadequate DNA damage caused by PARPi activated the Wnt signaling pathway and upregulated MYC. Further experiments indicated that the overexpression of β-catenin, especially its hyperphosphorylation at the Ser675 site activated the Wnt signaling pathway and mediated PARPi resistance, which could be strongly inhibited by the combined treatment with CDK4/6i.Conclusions: Our data provide a rationale for the clinical evaluation of the therapeutic synergy of PARPi and CDK4/6i in BRCAmut/TNBCs with high Wnt signaling activation, high MYC expression and do not respond to PARPi monotherapy.

show abstract

Section: Cdk4/6i Results In Defective G2 Cell Cycle-dependent Dna Repsupporting

confidence: 87%

Efficacy and Mechanism of the Combination of PARP and CDK4/6 Inhibitors in the Treatment of Triple-negative Breast Cancer

Zhu

CHEN

Huang

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The observed increase on cellular senescence induced by both drugs could be linked to apoptosis resistance mechanisms(15,18). As proposed by other groups(17,19,20), our results reinforce the cytostatic mechanism of action of CDK4/6 inhibitors and underscore that these should be given sequentially after completing chemotherapy treatment(21). However, the low cell death observed in vitro does not eliminate the possibility that palbociclib, by inducing senescence in a few cells, may promote in vivo cytotoxicity mediated by Natural Killer cells.…”

supporting

confidence: 89%

Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma

Aliagas

Alay

Martínez-Iniesta

et al. 2021

Preprint

View full text Add to dashboard Cite

There is no effective therapy for patients with malignant pleural mesothelioma (MPM) who progressed to platinum-based chemotherapy and immunotherapy. Here, we investigate the antitumor activity of CDK4/6 inhibitors using in vitro and in vivo preclinical models of MPM. Based on publicly available transcriptomic data of MPM, patients with CDK4 or CDK6 overexpression had shorter overall survival. Treatment with abemaciclib or palbociclib at 100 nM significantly decreased cell proliferation in all cell models. Both CDK4/6 inhibitors significantly induced G1 cell cycle arrest thereby increasing cell senescence and increased the expression of interferon signaling pathway and tumor antigen presentation process in culture models of MPM. In vivo preclinical studies showed that palbociclib significantly reduced tumor growth and prolonged overall survival in a platinum-naive and platinum resistant MPM mouse model. Treatment of MPM with CDK4/6 inhibitors decreased cell proliferation, mainly by promoting cell cycle arrest at G1 and by induction of cell senescence. Our preclinical studies provide evidence for evaluating CDK4/6 inhibitors in the clinic for the treatment of MPM.

show abstract

“…CDK6 specific drugs may interfere with transcriptional responses downstream of CDK6 while leaving proliferation intact which might be exploited in drug combinations using chemotherapy. First studies propose a benefit of chemotherapy and CDK4/6 inhibition depending on the sequential administration 87 . Although the versatile function of CDK6 in disease and tumor progression has been investigated in depth over the last decades, further studies are needed to improve selective cancer treatment and find novel effective synergistic combinations to prevent drug tolerance and resistance.…”

Section: Discussionmentioning

confidence: 99%

The role of CDK6 in cancer

Nebenfuehr

Kollmann

Sexl

2020

Intl Journal of Cancer

111

View full text Add to dashboard Cite

The regulation and function of cyclin-dependent kinase 6 (CDK6)-and cyclin-dependent kinase 4 (CDK4)-cyclin complexes are commonly altered with enhanced kinase activity found in hematopoietic malignancies, breast cancer and melanoma making CDK4 and CDK6 attractive targets for therapeutic interference. Although dual CDK4/6 inhibitors have revolutionized treatment of breast cancer patients and reveal promising results in several solid tumors and hematological malignancies, there is a need for novel compounds targeting the versatile kinase-independent functions of CDK6 to improve cancer treatment. The following review summarizes the latest findings on CDK6 in cancer development and discusses novel therapeutic approaches to selectively inhibit CDK6s function as a transcriptional regulator.

show abstract

CDK4/6 Inhibitors Impair Recovery from Cytotoxic Chemotherapy in Pancreatic Adenocarcinoma

Cited by 59 publications

References 0 publications

Efficacy and Mechanism of the Combination of PARP and CDK4/6 Inhibitors in the Treatment of Triple-negative Breast Cancer

Efficacy and Mechanism of the Combination of PARP and CDK4/6 Inhibitors in the Treatment of Triple-negative Breast Cancer

Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma

The role of CDK6 in cancer

Contact Info

Product

Resources

About

CDK4/6 Inhibitors Impair Recovery from Cytotoxic Chemotherapy in Pancreatic Adenocarcinoma

Cited by 59 publications

References 0 publications

Efficacy and Mechanism of the Combination of PARP&nbsp;and CDK4/6 Inhibitors in the Treatment of Triple-negative Breast Cancer

Efficacy and Mechanism of the Combination of PARP&nbsp;and CDK4/6 Inhibitors in the Treatment of Triple-negative Breast Cancer

Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma

The role of CDK6 in cancer

Contact Info

Product

Resources

About

Efficacy and Mechanism of the Combination of PARP and CDK4/6 Inhibitors in the Treatment of Triple-negative Breast Cancer

Efficacy and Mechanism of the Combination of PARP and CDK4/6 Inhibitors in the Treatment of Triple-negative Breast Cancer