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.2020.01.007

Cited by 128 publications

(84 citation statements)

References 67 publications

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“…Furthermore, combinational inhibition of both CDK4 and CDK6 is expected to have an even greater benefit to the clinical outcomes of PDAC patients [ 52 ]. It has been shown that an approach which uses CDK4/6 inhibitors after taxanes more effectively slows proliferation of PDAC cells [ 53 ]. Since G2M pathway score can accurately assess the cell cycle activity, we cannot help but speculate that the score may be useful as a biomarker for patient selection for CDK4/6 inhibition for pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection

Oshi

Newman

Tokumaru

et al. 2020

Cancers

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Pancreatic cancer is highly mortal due to uncontrolled cell proliferation. The G2M checkpoint pathway is an essential part of the cell cycle. We hypothesized that a high G2M pathway score is associated with cell proliferation and worse survival in pancreatic cancer patients. Gene set variation analysis using the Hallmark G2M checkpoint gene set was used as a score to analyze a total of 390 human pancreatic cancer patients from 3 cohorts (TCGA, GSE62452, GSE57495). High G2M score tumors enriched other cell proliferation genes sets as well as MKI67 expression, pathological grade, and proliferation score. Independent of other prognostic factors, G2M score was predictive of disease-specific survival in pancreatic cancer. High G2M tumor was associated with high mutation rate of KRAS and TP53 and significantly enriched these pathway gene sets, as well as high infiltration of Th2 cells. High G2M score consistently associated with worse overall survival in 3 cohorts, particularly in R1/2 resection, but not in R0. High G2M tumor in R1/2 highly enriched metabolic and cellular components’ gene sets compared to R0. To our knowledge, this is the first study to use gene set variation analysis as a score to examine the clinical relevancy of the G2M pathway in pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection

Oshi

Newman

Tokumaru

et al. 2020

Cancers

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“…First studies propose a benefit of chemotherapy and CDK4/6 inhibition depending on the sequential administration. 87…”

Section: Cdk6 In Melanomamentioning

confidence: 99%

The role of CDK6 in cancer

Nebenfuehr

Kollmann

Sexl

2020

Intl Journal of Cancer

122

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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.

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“…Due to their cytostatic action, CDK4/6 inhibitors will be ineffective as single agents and, thus, need to be applied as part of combination treatments with targeted compounds such as MTOR inhibitors or as part of a scheduled regimen with classical chemotherapeutics [75]. Classically seen as a driver of cell cycle progression by phosphorylating and inactivating RB1, recent findings point to a much more complex role by coordinating multiple cellular processes ranging from metabolism over DNA integrity to antigen processing and presentation [76][77][78][79][80][81][82][83]. Given this complexity it may not be a surprise that leukaemic fusion proteins do target such central cellular relais station.…”

Section: Therapeutic Targeting Of the Cell Cycle In Amlmentioning

confidence: 99%