Biology of CDK4/6 Inhibition
Geoffrey Shapiro, M.D., Ph.D.
Early Drug Development Center
Dana-Farber Cancer Institute
Geoffrey Shapiro, MD, PhD
Consulting Fees (e.g., advisory boards):
G1 Therapeutics, Millenium, Vertex, Mallinkrodt
I intend to reference unlabeled/unapproved uses of
drugs or products in my presentation. Please list name
of device/drug and unlabeled/unapproved use:
Palbociclib (PD0332991), LY2835219, LEE011
CDKs participate in cell cycle progression
and cellular transcription
CDK4/6 Selective
CDK2/1 +/- 7, 9
Sausville, Trends Mol Med, 2002
CDK Inhibitor Compounds
CDK1/2/9 or pan-CDK
CDK4/6 Selective
Palbociclib (PD-0332991)
LY2835419
LEE011
•
•
Synthetic senescence (ER+
breast cancer; KRAS-mutated
NSCLC)
CDK4/6 dependence for
viability: Burkitt Lymphoma, TCell Leukemia
Dinaciclib
Seliciclib
CYC-065
BAY1000394
AT7519
•
Mcl-1, Myc and Cyclin Edependent tumors may be
vulnerable to CDK9, CDK1
and CDK2 inhibition,
respectively
Lecture Outline
• Consequences of CDK4/6 inhibition in preclinical
models and selected clinical trials (breast ca,
NSCLC, glioblastoma, hematologic malignancies,
liposarcoma)
• Resistance to CDK4/6 inhibition
• CDK4/6 inhibitor-based combinations
• CDK4/6 inhibition and the DNA damage response
(DNA repair pathways and protection of nontransformed cells)
Consequences of CDK4/6 Inhibition
Fernandez et al, JCO 2005
CDK4/6 activity is linked to senescence
suppression via stabilization of FOXM1 and
CDK4/6 inhibition induces senescence
Anders et al. Cancer Cell 2011: 20: 620-634
Genetic or pharmacologic ablation of cyclin D-CDK4/6
activity induces senescence in mouse model of
HER2-driven breast cancer
Choi et al. Cancer Cell 2012; 22: 438-451
ER+ breast cancer cell lines are highly sensitive
to CDK4/6-inhibitor-mediated growth arrest
Finn et al. Breast Ca Res 2009; 11: R77
Dean et al. Oncogene 2010; 29:4018-32
CDK4 ablation or inhibition arrests growth and induces
senescence in a mouse model of Kras-driven NSCLC
Puyol et al. Cancer Cell 2010; 18: 63-73
Cytostatic responses to palbociclib in Mantle Cell
Lymphoma with delayed tumor responses
Leonard et al. Blood 2012; 119: 4597-607
Cytostatic responses to palbociclib in CDK4-amplified
liposarcoma with delayed tumor regressions
Dickson et al. J Clin Oncol 2013; 31: 2024-8
Abrupt apoptosis in Notch-driven T-cell ALL by
cyclin D3 ablation or CDK4/6 inhibition
Choi et al. Cancer Cell 2012; 22: 438-451
Sawai et al. Cancer Cell 2012; 22: 452-65
Burkitt Lymphoma Cells have frequent CCND3
mutation, Cyclin D3-CDK6 dependence and abrupt
cytotoxicity after CDK4/6 inhibition
Schmitz et al. Nature 2012; 490: 116-20
Senescence vs. Apoptotic Responses
to CDK4/6 Inhibition
Malumbres M., Cancer Cell, 2012; 22: 419-20
Possible cytotoxic mechanisms
(1) Role of CDK6 as a chromatin-bound NF-κB co-factor; (2) kinase-indpendent function
Of CDK6 in angiogenesis; (3) synthetic lethality of CDK4/6 inhibition with Notch activation
Handschick et al. Mol Cell 2014; 53: 193-208; Kollmann et al. Cancer Cell 2013; 24: 167-81;
Choi et al. Oncotarget 2013; 4: 176-7
Primary resistance to CDK4/6 Inhibition
• Rb-negativity
• Lack of co-deletion of CDKN2A/CDKN2C in
glioblastoma
Wiedermeyer et al. PNAS 2010; 107: 11501-6
Adaptation and Acquired Resistance
Leonard et al. Blood 2012; 119: 4597-607
Adaptation and Acquired Resistance: CDK2
activation and re-phosphorylation of Rb
Reduced p27Kip1 activates CDK2 and promotes Rb phosphorylation and
reversal of G1 arrest
Wang et al. Blood 2007; 110: 2075-83
CDK4/6 inhibitor combinations:
hormonal therapy
Finn et al. Breast Ca Res 2009; 11: R77
Finn et al. SABCS, 2012
CDK4/6 inhibitor combinations:
signal transduction inhibitors (MEKi)
Kwong et al. Nat Med 2012; 18: 1503-10
CDK4/6 inhibitor combinations:
signal transduction inhibitors (PI3Kδi)
pG1 induced by CDK4/6 inhibition
induces PIK3IP1 and therefore
amplifies and sustains PI3Kδ in
response to GS-1101 (idelalisib)
Chiron et al. Cell Cycle 2013;12:1892-1900
CDK4/6 Inhibition and possible NHEJ dependence
Kee Y , D'Andrea A D Genes Dev, 2010;
Dean, Knudsen, J Biol Chem, 2012
CDK4/6 Inhibition as chemo-protection in
treatment of Rb-negative cancers
Rb-negative tumor model
Roberts et al. JNCI 2012; 104:476-87
Summary
• Well-tolerated orally-bioavailable CDK4/6 inhibitors are under
development
• CDK4/6 inhibition can induce (1) cell cycle arrest; (2)
senescence; (3) delayed tumor regression; (4) abrupt
cytotoxicity
• Rb phosphorylation and FLT-PET are PD endpoints
• Primary resistance is related to the status of the Rb-axis
• Acquired resistance is likely related in part to circumvention of
cell cycle inhibition by other CDK family members
• Combination strategies are particularly promising: (1)
hormonal therapy in breast cancer; (2) combinations with
signal transduction inhibitors, including MEK inhibitors in
RAS-driven disease
• CDK4/6 inhibitor-mediated arrest may induce NHEJ
dependence and limit the availability of homologous
recombination
• CDK4/6 inhibition may protect gut and marrow and therefore
limit toxicity of DNA damaging agents, while not affecting the
efficacy of those agents against Rb-negative tumor cells