Targeting CDK4 and CDK6: From Discovery to Therapy

May combine two claims.

In young animals under normal physiological conditions, p16INK4a is not expressed, but it is induced by hyperproliferative stress signals whose oncogenic effects are countered by p16-induced cell cycle arrest.

“Under normal physiological circumstances in young animals, p16INK4a is not expressed; however, it is induced by a variety of hyperproliferative stress signals whose oncogenic effects are countered by p16INKa-induced cell cycle arrest (47).”

• cites [47] Serrano, 1997, Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a, Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Release from the chaperone complex allows CDK4 to interact with D-type cyclins or to dimerize with p16INK4a, yielding inactive CDK4.

“Release from the chaperone complex enables CDK4 to interact with D-type cyclins, or alternatively, to dimerize with p16INK4a, yielding inactive CDK4.”

May combine two claims.

Hypophosphorylated active RB restricts proliferation and acts as a potent tumor suppressor, and its growth-suppressive function can be inactivated by binding to DNA tumor virus oncoproteins HPV E7, adenovirus E1A, and SV40 T antigen.

“The role of hypophosphorylated (active) RB to restrict proliferation and act as a potent tumor suppressor gene was highlighted by studies indicating that RB's growth suppressive function could be inactivated by its binding to DNA tumor virus oncoproteins (human papillomavirus E7, adenovirus E1A, and SV40 T antigen) (24-27).”

• cites [24] Whyte, 1988, Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product, Nature sourceNot checked yet

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• cites [25] Dyson, 1989, The human papilloma virus-16 E7-oncoprotein is able to bind to the retinoblastoma gene product, Science sourceNot checked yet

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• cites [26] DeCaprio, 1988, SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene, Cell sourceNot checked yet

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• cites [27] Ludlow, 1989, SV40 large T antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family, Cell sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

Elucidating how signal transduction pathways activate CDK4/6 in different tumor types should enable combinatorial therapies that target cyclin D and CDK4/6 together to improve responses.

“The elucidation of how signal transduction pathways activate CDK4/6 in different tumor types should pave the way for combinatorial therapies that target both cyclin D and CDK4/6 simultaneously to improve therapeutic responses.”

May combine two claims.

Understanding how D-type cyclins act as environmental sensors helps explain differential CDK4/6 regulation and predicts interactions between mitogen signaling and CDK4/6 in normal and cancer cells.

“An understanding of how the three different D-type cyclins act as environmental sensors in responding dynamically to extracellular cues in various cell types helps to explain how CDK4/6 activities are differentially regulated, and predicts the basis of functional interactions between mitogen signaling pathways and CDK4/6 activity in both normal and cancer cells.”

Probably not a substantial claim: may not pass S3 (load-bearing).

CDK6, a related cyclin D-dependent kinase with similar properties, was identified two years later.

“A related cyclin D-dependent kinase, CDK6, with similar properties was identified two years later (12).”

• cites [12] Meyerson, 1994, Identification of G1 kinase activity for cdk6, a novel cyclin D partner, Mol Cell BiolNot checked yet

  Not checked in the free run.

May combine two claims.

CDK4 is a fastidious enzyme that phosphorylates RB and the RB-family proteins RB2 and RBL1, but very few other substrates, unlike CDKs 1 and 2, which phosphorylate many hundreds of proteins.

“Unlike CDKs 1 and 2 that phosphorylate many hundreds of cellular protein substrates (13), CDK4 is a surprisingly fastidious enzyme that has a restricted propensity to phosphorylate the retinoblastoma protein (RB1, hereafter RB) and two other RB-family proteins [RB2 (p130), RBL1 (p107)] (11, 14-16), but very few other substrates (17).”

• cites [13] Ubersax, 2003, Targets of the cyclin-dependent kinase Cdk1, Nature sourceNot checked yet

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• cites [11] Matsushime, 1992, Identification and properties of an atypical catalytic subunit (p34PSK-J3/Cdk4) for mammalian D type G1 cyclins, Cell sourceNot checked yet

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• cites [14] Kato, 1993, Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4, Genes Dev sourceNot checked yet

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• cites [15] Ewen, 1993, Functional interactions of the retinoblastoma protein with mammalian D-type cyclins, Cell sourceNot checked yet

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• cites [16] Burkhart, 2008, Cellular mechanisms of tumour suppression by the retinoblastoma gene, Nat Rev Cancer sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

HSP90 inhibition might complement CDK4 inhibitors in preventing RB phosphorylation and enforcing cell cycle arrest.

“Presumably, HSP90 inhibition might also complement CDK4 inhibitors in preventing RB phosphorylation and enforcing cell cycle arrest.”

Classified as probably not a substantial claim.

FDA approval of palbociclib with letrozole for breast cancer represents a long-sought success.

“FDA-approval of the CDK4/6 inhibitor palbociclib used with the aromatase inhibitor letrozole for breast cancer treatment highlights long sought success.”

May combine two claims.

p16INK4a expression inhibits RB phosphorylation and arrests cells in G1.

“expression of p16INK4a inhibited RB phosphorylation and arrested cells in the G1 phase of the cell cycle.”

• cites [32] Serrano, 1993, A new regulatory motif in cell-cycle control causing specific-inhibition of cyclin-D/Cdk4, Nature sourceNot checked yet

  Not checked in the free run.

May combine two claims.

CDKs 1 and 2 with cyclins E, A, and B drive progression through S and M phase, whereas cyclin D-dependent CDKs act in G1 to move quiescent or post-mitotic cells toward S phase.

“Although CDKs 1 and 2, in complexes with cyclins E, A, and B, drive cell cycle progression through S phase and M phase (mitosis), the cyclin D-dependent CDKs act during G1 phase to propel quiescent cells that have entered the cell cycle, or proliferating cells that have completed mitosis, toward S phase (Figure 1).”

Probably not a substantial claim: may not pass S4 (based).

The three D-type cyclins are expressed differentially, alone or together, in distinct cell lineages, where they assemble with CDK4 and CDK6 into active holoenzyme complexes.

“The three D-type cyclins (D1, D2, and D3) are differentially expressed, alone or in combination, in distinct cell lineages, where they assemble with CDK4 and CDK6 to form enzymatically active holoenzyme complexes.”

May combine two claims.

Hsc70 associates with newly synthesized cyclin D1 and is a component of the mature active cyclin D1-CDK4 complex.

“Hsc70 associates with newly synthesized cyclin D1 and is a component of the mature catalytically active cyclin D1-CDK4 complex (44).”

• cites [44] Diehl, 2003, Hsc70 regulates accumulation of cyclin D1 and cyclin D1-dependent protein kinase, Mol Cell Biol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

CDK4 was discovered and shown to bind and be enzymatically activated by any of the three D-type cyclins.

“The presumption that D-type cyclins might allosterically regulate a novel CDK was validated by the discovery of CDK4, which was revealed to physically bind to, and be enzymatically activated by, any of the three D-type cyclins (11).”

• cites [11] Matsushime, 1992, Identification and properties of an atypical catalytic subunit (p34PSK-J3/Cdk4) for mammalian D type G1 cyclins, Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In serum-deprived fibroblasts lacking endogenous D cyclin, ectopically expressed cyclin D1 does not associate with CDK4, but assembly occurs with constitutively active MEK.

“In serum-deprived fibroblasts lacking endogenous D cyclin expression, ectopically expressed cyclin D1 does not associate with CDK4 (28), but assembly of cyclin D-CDK complexes occurs in response to enforced expression of constitutively active MEK (43).”

• cites [28] Matsushime, 1994, D-type cyclin-dependent kinase activity in mammalian cells, Mol Cell BiolNot checked yet

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• cites [43] Cheng, 1998, Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1), Proc Natl Acad Sci U S A sourceNot checked yet

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May combine two claims.

RB is dephosphorylated at mitotic exit, hypophosphorylated in G1, and hyperphosphorylated and inactivated in late G1 through S phase to mitosis.

“RB is dephosphorylated as cells exit mitosis, and the hypophosphorylated form detected in G1 phase becomes hyperphosphorylated (inactivated) in late G1 and remains so throughout progression through S phase to mitosis (20-23) (Figure 1).”

• cites [20] Buchkovich, 1989, The retinoblastoma protein is phosphorylated during specific phases of the cell cycle, Cell sourceNot checked yet

  Not checked in the free run.

• cites [21] DeCaprio, 1989, The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element, Cell sourceNot checked yet

  Not checked in the free run.

• cites [22] Chen, 1989, Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation, Cell sourceNot checked yet

  Not checked in the free run.

• cites [23] Mihara, 1989, Cell cycle dependent regulation of phosphorylation of the human retinoblastoma gene product, Science sourceNot checked yet

  Not checked in the free run.

May combine two claims.

CCND1 is a target of translocation in certain tumors such as mantle cell lymphoma or is amplified in breast cancer, reinforcing that cyclin D1 and by presumption CDK4 are oncoproteins.

“In turn, the realization that CCND1 in particular was a target of translocation in certain tumors [for example, in mantle cell lymphoma (MCL)] or was amplified (for example, in breast cancer) reinforced the view that cyclin D1 (and, by presumption, CDK4) were oncoproteins.”

May combine two claims.

Cells lacking functional RB are resistant to p16INK4a-mediated cell cycle arrest, implying that CDK4/6-driven G1 progression requires RB.

“Importantly, cells lacking functional RB were resistant to p16INK4a-mediated cell cycle arrest, implying that the ability of CDK4 (and later, CDK6) to drive G1 phase progression required RB (33-35) and predicting that chemical CDK4/6 inhibitors would show efficacy only if RB were functionally intact.”

• cites [33] Lukas, 1995, Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16, Nature sourceNot checked yet

  Not checked in the free run.

• cites [34] Medema, 1995, Growth suppression by p16ink4 requires functional retinoblastoma protein, Proc Natl Acad Sci U S A sourceNot checked yet

  Not checked in the free run.

• cites [35] Koh, 1995, Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition, Nature sourceNot checked yet

  Not checked in the free run.

May combine two claims.

p16INK4a binds and potently inhibits cyclin D-CDK4 kinase activity but spares holoenzyme complexes containing other CDKs.

“Key features were that p16INK4a bound to and potently inhibited cyclin D-CDK4 kinase activity but spared holoenzyme complexes containing other CDKs, and that expression of p16INK4a inhibited RB phosphorylation and arrested cells in the G1 phase of the cell cycle.”

• cites [32] Serrano, 1993, A new regulatory motif in cell-cycle control causing specific-inhibition of cyclin-D/Cdk4, Nature sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Withdrawal of palbociclib after several weeks was accompanied by tumor regrowth, but the re-emerging cancers remained drug-sensitive, suggesting that recurring tumors did not acquire therapeutic resistance.

“Although withdrawal of palbociclib after several weeks was accompanied by tumor regrowth, the re-emerging cancers remained drug-sensitive, suggesting that recurring tumors did not acquire therapeutic resistance.”

• cites [66] Fry, 2004, Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts, Mol Cancer Ther sourceNot checked yet

  Not checked in the free run.

• cites [67] Toogood, 2005, Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6, J Med Chem sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Treated breast, colon, and lung cancer cell lines primarily driven by cyclin D1-CDK4, and myeloid and lymphoid leukemia cells depending on cyclins D2/D3 and CDK6, accumulated in G1, lost Ki67, and downregulated E2F target genes, with IC50 values of 40 to 170 nM.

“Treated breast, colon, and lung cancer cell lines, which are primarily driven by cyclin D1-CDK4, as well as myeloid and lymphoid leukemia cells that primarily depend on cyclins D2/D3 and CDK6, accumulated in G1 phase, exhibited loss of the proliferation marker Ki67, and downregulated canonical E2F target genes (IC50 values for cultured cells: 40 to 170 nM).”

• cites [66] Fry, 2004, Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts, Mol Cancer Ther sourceNot checked yet

  Not checked in the free run.

• cites [67] Toogood, 2005, Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6, J Med Chem sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In several xenograft models, palbociclib induced tumor stasis or regression and was tolerated without significant toxicities at daily doses up to 150 mg/kg for up to 50 days.

“In several xenograft models, the drug was efficacious in inducing tumor stasis or regression and was tolerated without significant toxicities at daily doses up to 150 mg/kg for up to 50 days of treatment (66, 67).”

• cites [66] Fry, 2004, Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts, Mol Cancer Ther sourceNot checked yet

  Not checked in the free run.

• cites [67] Toogood, 2005, Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6, J Med Chem sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Certain cyclin D mutants or C-terminally truncated D1b variants lacking the Thr-286 codon are retained in the nucleus during S phase and are proposed to confer a neo-oncogenic function that triggers DNA re-replication, aneuploidy, and tumorigenesis.

“Moreover, certain cyclin D mutants or C-terminally truncated variants encoded by an alternatively spliced mRNA (D1b) that lacks the Thr-286 codon are retained in the nucleus during S phase and are proposed to confer a neo-oncogenic function that triggers DNA re-replication, aneuploidy, and tumorigenesis (59-61).”

• cites [59] Aggarwal, 2007, Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication, Genes Dev sourceNot checked yet

  Not checked in the free run.

• cites [60] Li, 2015, PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers, Cancer Discov sourceNot checked yet

  Not checked in the free run.

• cites [61] Augello, 2015, Consequence of the tumor-associated conversion to cyclin D1b, EMBO Mol Med sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Palbociclib is an orally bioavailable, low nanomolar reversible CDK4/6 inhibitor with no significant activity against a wide panel of other kinases, and CDK2 and CDK1 are more than 1000-fold less sensitive.

“Palbociclib is an orally bioavailable, low nanomolar reversible inhibitor of CDK4/6 (Table 1), which exhibited no significant activity against a wide panel of other kinases; these included cyclin E- and A-driven CDK2 and cyclin B-CDK1 that are more than 1000-fold less sensitive to the drug (Table 1).”

• cites [66] Fry, 2004, Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts, Mol Cancer Ther sourceNot checked yet

  Not checked in the free run.

• cites [67] Toogood, 2005, Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6, J Med Chem sourceNot checked yet

  Not checked in the free run.

May combine two claims.

PI3K/AKT-mediated inhibition of cyclin D1 Thr-286 phosphorylation prevents nuclear export of cyclin D1-CDK complexes and blocks cyclin D1 recognition by the FBX4-containing ubiquitin ligase that triggers cyclin D degradation.

“PI3K/AKT-mediated Inhibition of cyclin D1 Thr-286 phosphorylation prevents the nuclear export of cyclin D1-CDK complexes and blocks cyclin D1 recognition by the FBX4-containing ubiquitin ligase that triggers cyclin D degradation (55-58).”

• cites [55] Diehl, 1997, Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway, Genes Dev sourceNot checked yet

  Not checked in the free run.

• cites [56] Diehl, 1998, Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization, Genes Dev sourceNot checked yet

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• cites [57] Alt, 2000, Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation, Genes Dev sourceNot checked yet

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• cites [58] Lin, 2006, Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF(FBX4-alphaB crystallin) complex, Mol Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In a pilot mantle cell lymphoma study, substantial reductions in summed FLT-PET SUVmax, RB phosphorylation, and Ki-67 expression occurred after 3 weeks in most patients, with significant correlations among these endpoints.

“Substantial reductions in the summed FLT-PET maximal standard uptake value (SUVmax), as well as in RB phosphorylation and Ki-67 expression, occurred after 3 weeks in most patients, with significant correlations among these end points.”

• cites [75] Leonard, 2012, Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma, Blood sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In the phase 1 experience, a partial response occurred in a patient with growing teratoma syndrome, and later stable disease was noted in 19 of 74 patients with advanced solid tumors, with nine patients receiving ten or more cycles.

“In the phase 1 experience, a partial response was achieved in a patient with growing teratoma syndrome (73), with clinical benefit later confirmed in a larger group of patients with teratoma (74): stable disease was noted in 19 of 74 patients with advanced solid tumors, with nine patients receiving ten or more cycles on either the 3/1 or 2/1 schedule.”

• cites [73] Vaughn, 2009, Treatment of growing teratoma syndrome, N Engl J Med sourceNot checked yet

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• cites [74] Vaughn, 2015, Phase 2 trial of the cyclin-dependent kinase 4/6 inhibitor palbociclib in patients with retinoblastoma protein-expressing germ cell tumors, Cancer sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Patients with prolonged clinical benefit in mantle cell lymphoma had marked first-cycle reductions in FLT SUVmax and phospho-RB/Ki67, but such decreases also occurred in patients who did not achieve prolonged benefit, suggesting population heterogeneity in responses after initial CDK4/6 inhibition.

“Although those patients with prolonged clinical benefit demonstrated marked first-cycle reductions in summed FLT SUVmax and in expression of phospho-RB and Ki67, such decreases also occurred in patients who did not go on to achieve prolonged benefit, suggesting population heterogeneity in responses after initial CDK4/6 inhibition.”

• cites [75] Leonard, 2012, Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma, Blood sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Tumor xenografts lacking CDKN2A were sensitive to palbociclib, whereas those lacking functional RB were refractory.

“Tumor xenografts lacking CDKN2A were sensitive to drug, whereas those lacking functional RB were refractory to palbociclib treatment.”

• cites [66] Fry, 2004, Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts, Mol Cancer Ther sourceNot checked yet

  Not checked in the free run.

• cites [67] Toogood, 2005, Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6, J Med Chem sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Inactivation of individual cyclin D, Cdk4/6, and Ink4a genes in mice causes specific developmental defects but establishes that their functions are nonessential for the cell cycle per se.

“Despite the high frequency of mutations epistatically targeting the RB signaling pathway in cancer cells, inactivation of the individual cyclin D, Cdk4/6, and Ink4a genes in mice, while leading to specific developmental defects when disrupted alone or in combination, established that their functions were nonessential for the cell cycle per se (62-64).”

• cites [62] Malumbres, 2004, Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6, Cell sourceNot checked yet

  Not checked in the free run.

• cites [63] Sherr, 2004, Living with or without cyclins and cyclin-dependent kinases, Genes Dev sourceNot checked yet

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• cites [64] Kozar, 2004, Mouse development and cell proliferation in the absence of D-cyclins, Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

One liposarcoma patient with a de-differentiated tumor achieved partial response at 74 weeks and then complete response; another had reduction of a de-differentiated component within a well-differentiated lesion resulting in a 30% tumor decrease over 1 year.

“One patient with a de-differentiated tumor achieved partial response at 74 weeks and went on to achieve a complete response; another patient demonstrated reduction of a de-differentiated component within a well-differentiated lesion that resulted in a 30% tumor decrease over a 1-year period.”

• cites [77] Dickson, 2013, Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Five of 17 heavily pretreated mantle cell lymphoma patients achieved progression-free survival greater than 1 year (range 15-30 months), with one complete and two partial responses.

“Five of 17 heavily pretreated patients (including those who had received prior chemotherapy (bortezomib and stem cell transplant), achieved progression-free survival (PFS) of > 1 year (range, 15-30 months), with one complete and two partial responses.”

• cites [75] Leonard, 2012, Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma, Blood sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Regressions were noted in four liposarcoma patients; in two instances they were documented late in treatment, reminiscent of delayed responses in the mantle cell lymphoma study.

“Additionally, regressions were noted in four patients; in two instances, these were documented late in the treatment course, reminiscent of delayed responses observed in the MCL study.”

• cites [77] Dickson, 2013, Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Among 30 liposarcoma patients treated on the 2/1 schedule, 66% were progression-free at 12 weeks, exceeding the protocol pre-defined endpoint of 40%.

“Among 30 patients treated on the 2/1 schedule, 66% were progression-free at 12 weeks, exceeding the protocol pre-defined endpoint of 12-week PFS of 40%.”

• cites [77] Dickson, 2013, Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Cyclin D transcription, assembly with CDK4/6, nuclear transport, and stability are each mitogen-dependent steps governed by distinct signaling pathways.

“In short, cyclin D transcription, assembly with CDK4/6, nuclear transport, and stability are each mitogen-dependent steps governed by distinct signaling pathways.”

May combine two claims.

Inactivation of these genes can prevent oncogene-induced tumor development in mouse models, reinforcing that these enzymes might be suitable cancer-specific drug targets.

“In contrast, the demonstration that inactivation of these genes can prevent oncogene-induced tumor development in mouse models reinforced the view that these enzymes might be suitable cancer-specific drug targets (65).”

• cites [65] Malumbres, 2009, Cell cycle, CDKs and cancer: a changing paradigm, Nat Rev Cancer sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Palbociclib exhibited linear pharmacokinetics, with a median time to maximal concentration of 4 hours and a mean plasma half-life of 26.5 hours.

“Palbociclib exhibited linear pharmacokinetics, with a median time to maximal concentration (Tmax) of 4 hours, and was eliminated with a mean plasma half-life of 26.5 hours (Table 1).”

May combine two claims.

Other side effects of palbociclib were mild, including fatigue, diarrhea, anemia, and nausea, with overall good tolerability on both dosing schedules.

“Other side effects were mild, including fatigue, diarrhea, anemia, and nausea, with overall good tolerability on both dosing schedules.”

• cites [69] Schwartz, 2011, Phase I study of PD0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1), Br J Cancer sourceNot checked yet

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• cites [70] Flaherty, 2012, Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD0332991, administered using a 21-day schedule in patients with advanced cancer, Clin Cancer Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Parke-Davis chemists developed PD0332991, which became Pfizer's palbociclib.

“Soon thereafter, chemists at Parke-Davis developed a specific CDK inhibitor (PD0332991) that would eventually become Pfizer's Palbociclib (IBrance™) (66, 67).”

• cites [66] Fry, 2004, Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts, Mol Cancer Ther sourceNot checked yet

  Not checked in the free run.

• cites [67] Toogood, 2005, Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6, J Med Chem sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Reasons for abemaciclib's reduced hematologic and other non-hematologic toxicities are under investigation but may relate to greater CDK4 over CDK6 selectivity, greater potency and potential CDK9 targeting, and/or CNS distribution.

“The reasons for reduced hematologic toxicity and other observed non-hematologic toxicities are under active investigation but may be related to a greater selectivity for CDK4 over CDK6 with abemaciclib (88), its greater relative potency and potential to target CDK9 (Table 1), and/or its distribution into the central nervous system (93).”

• cites [88] Gelbert, 2014, Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine, Invest New Drugs sourceNot checked yet

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• cites [93] Raub, 2015, Abemaciclib (LY2835219) is an oral inhibitor of the cyclin-dependent kinases 4/6 that crosses the blood-brain barrier and demonstrates In vivo activity against intracranial human brain tumor xenografts, Drug Metab Dispos sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Abemaciclib shows dose-proportional pharmacokinetics, median time to maximal plasma concentration 4-6 hours, and terminal elimination half-life 17-38 hours.

“The agent demonstrates dose-proportional pharmacokinetics, with a median time to maximal plasma concentration of 4-6 hours and terminal elimination half-life ranging 17-38 hours.”

• cites [92] Shapiro, 2013, A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In a Phase 2 study of palbociclib in RB-positive advanced breast cancer, one HR+/HER2− patient achieved partial response and five had stable disease for at least 6 months, with median PFS of 3.8 and 1.5 months for the HR+/HER2− and HR−/HER2− groups, respectively.

“Of the HR+/HER2− group, one patient achieved partial response and five had stable disease for ≥ 6 months, with median PFS of 3.8 and 1.5 months for the HR+/HER2− and HR−/HER2− groups, respectively.”

• cites [82] DeMichele, 2015, CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment, Clin Cancer Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

MDM2 turnover depends on its E3 ligase activity and ATRX expression, and is postulated to facilitate stabilization of a senescence-activating protein or proteins in a p53-independent fashion.

“MDM2 turnover was found to depend on its E3 ligase activity and the expression of ATRX, and is postulated to facilitate stabilization of a senescence-activating protein(s) in a p53-independent fashion.”

• cites [80] Kovatcheva, 2015, MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition, Oncotarget sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Abemaciclib causes diarrhea and hematologic toxicity; diarrhea is manageable with supportive medications or dose reduction, and hematologic toxicity is milder than with other compounds, allowing continuous daily dosing.

“Diarrhea and hematologic toxicity also occur with this agent, although the former is manageable with supportive medications and/or dose reduction, and the latter is milder than with the other compounds, allowing continuous daily dosing without interruption.”

• cites [92] Shapiro, 2013, A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Predicted side effects of targeted therapy may involve glucose intolerance based on pancreatic β-cell requirements for CDK4 and p16INK4a effects on islet regeneration.

“predicted side effects of targeted therapy may involve glucose intolerance, based on requirements of pancreatic β-cells for CDK4 (85, 86) and effects of p16INK4a on age-dependent islet cell regeneration (87)”

• cites [85] Rane, 1999, Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia, Nat Genet sourceNot checked yet

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• cites [86] Tsutsui, 1999, Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kip1) activity, Mol Cell Biol sourceNot checked yet

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• cites [87] Krishnamurthy, 2006, p16INK4a induces an age-dependent decline in islet regenerative potential, Nature sourceNot checked yet

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May combine two claims.

Proteolytic turnover of MDM2 was required for induction of senescence, whereas cell lines that only underwent transient G1 arrest did not reduce MDM2 in response to palbociclib.

“Proteolytic turnover of MDM2 was required for the induction of senescence, whereas cell lines that only underwent transient G1 arrest did not reduce MDM2 in response to palbociclib.”

• cites [80] Kovatcheva, 2015, MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition, Oncotarget sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Abemaciclib's recommended phase 2 dose is 200 mg twice daily; both once daily and twice daily schedules were evaluated.

“Both once daily and twice daily schedules have been evaluated with a recommended phase 2 dose of 200 mg twice daily (92).”

• cites [92] Shapiro, 2013, A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

All three inhibitors compete with ATP for binding to CDK4/6, and potency and specificity differences reflect chemical structure differences.

“All three inhibitors compete for binding of ATP to CDK4/6, so variations in potency and specificity reflect their somewhat different chemical structures”

• cites [1] Asghar, 2015, The history and future of targeting cyclin-dependent kinases in cancer therapy, Nat Rev Drug Discov sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In ribociclib Phase 1, among 85 patients, dose-limiting toxicities occurred in ten, including neutropenia, thrombocytopenia, pulmonary embolism, hyponatremia, QTcF prolongation, and elevated creatinine, leading to a recommended phase 2 dose of 600 mg daily on the 3/1 schedule.

“Among 85 patients treated, dose limiting toxicities occurred in ten, including neutropenia, thrombocytopenia, pulmonary embolism, hyponatremia, QTcF prolongation and elevated creatinine, resulting in a recommended phase 2 dose of 600 mg daily on the 3/1 schedule.”

• cites [90] Infante, 2013, Abstract 276: phase 1 multicenter, open-label, dose-escalation study of LEE011, an oral inhibitor of cyclin-dependent kinase 4/6, in patients with advanced solid tumors or lymphomas, Mol Cancer Ther sourceNot checked yet

  Not checked in the free run.

• cites [91] Infante, 2014, A phase 1 study of the single-agent CDK4/6 inhibitor LEE011 in patients with advanced solid tumors and lymphomas, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Only one of the partial responders received concomitant hormonal therapy, suggesting a higher response rate for abemaciclib as a single agent than palbociclib.

“Only one of the partial responders received concomitant hormonal therapy, suggesting a higher response rate for abemaciclib as a single agent than palbociclib.”

• cites [92] Shapiro, 2013, A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

• cites [95] Patnaik, 2014, Abstract CT232: clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer, Cancer Res sourceNot checked yet

  Not checked in the free run.

• cites [96] Tolaney, 2015, Abstract P5-19-13: clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer, Cancer Res sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Diabetogenic effects in long-term treated patients have not been reported.

“Although diabetogenic effects in long-term treated patients have not been reported”

May combine two claims.

In that trial, 24% of patients had treatment interruption and 51% had dose reduction, all for cytopenias.

“Notably, in this trial 24% of patients had treatment interruption and 51% had dose reduction, all for cytopenias.”

• cites [82] DeMichele, 2015, CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment, Clin Cancer Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Preclinical data with palbociclib demonstrated substantial sensitivity of hormone receptor-positive cell lines compared to hormone receptor-negative cell lines, in part related to a higher incidence of RB-negativity in the latter breast cancer subgroup.

“Preclinical data utilizing palbociclib demonstrated the substantial sensitivity of hormone receptor (HR)-positive cell lines, compared to HR-negative cell lines, in part related to a higher incidence of RB-negativity in the latter breast cancer subgroup (81).”

• cites [81] Finn, 2009, PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro, Breast Cancer Res sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

CCND1 amplification and CDKN2A loss may contribute to determining response to letrozole alone.

“Possibly, CCND1 amplification and CDKN2A loss may contribute to determining response to letrozole alone”

• cites [68] Musgrove, 2011, Cyclin D as a therapeutic target in cancer, Nat Rev Cancer sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Abemaciclib is widely distributed, with cerebrospinal fluid concentrations approximating plasma concentrations.

“Abemaciclib is widely distributed (93) such that concentrations can be detected in cerebrospinal fluid that approximate those in plasma (92)”

• cites [92] Shapiro, 2013, A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

• cites [93] Raub, 2015, Abemaciclib (LY2835219) is an oral inhibitor of the cyclin-dependent kinases 4/6 that crosses the blood-brain barrier and demonstrates In vivo activity against intracranial human brain tumor xenografts, Drug Metab Dispos sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In PALOMA-3 interim analysis, PFS was 9.2 months with palbociclib-fulvestrant versus 3.8 months with placebo-fulvestrant, with hazard ratio 0.42.

“an interim analysis reported PFS of 9.2 months with palbociclib-fulvestrant and 3.8 months with placebo-fulvestrant (hazard ratio 0.42)”

• cites [84] Turner, 2015, Palbociclib in hormone-receptor-positive advanced breast cancer, N Engl J Med sourceNot checked yet

  Not checked in the free run.

May combine two claims.

200 mg twice daily was selected for further abemaciclib development to ensure persistent target coverage over the dosing interval, as preclinical PK/PD modeling in mice showed this was important.

“Therefore, 200 mg twice daily was selected as the dose and schedule for further development, to ensure persistent target coverage over the dosing interval, as was shown to be important in preclinical pharmacokinetic/pharmacodynamics modeling in mice bearing human tumor xenografts (94).”

• cites [94] Tate, 2014, Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts, Clin Cancer Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In the entire PALOMA-1 population of 165 patients, median PFS was 10.2 months with letrozole alone versus 20.2 months with palbociclib plus letrozole, with hazard ratio 0.488.

“When the entire population of 165 patients is considered, median PFS was 10.2 months for letrozole alone and 20.2 months for the combination (hazard ratio 0.488)”

• cites [83] Finn, 2015, The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study, Lancet Oncol sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Abemaciclib may be useful for treating brain tumors.

“forecasting its potential use in treating brain tumors”

• cites [92] Shapiro, 2013, A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

• cites [93] Raub, 2015, Abemaciclib (LY2835219) is an oral inhibitor of the cyclin-dependent kinases 4/6 that crosses the blood-brain barrier and demonstrates In vivo activity against intracranial human brain tumor xenografts, Drug Metab Dispos sourceNot checked yet

  Not checked in the free run.

May combine two claims.

PALOMA-3 enrolled pre- and peri-menopausal patients, and benefit of the combination was observed across groups.

“This study enrolled pre- and peri-menopausal patients, with benefit of the combination observed across groups.”

• cites [84] Turner, 2015, Palbociclib in hormone-receptor-positive advanced breast cancer, N Engl J Med sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In that breast cancer trial, HR+ patients who had received more than two lines of anti-estrogen therapy had significantly longer PFS than those who had received fewer therapeutic cycles (5 vs 2 months); prior cytotoxic exposure did not affect outcome.

“Stratification related to degree of prior treatment demonstrated that patients with HR+ tumors who had received more than two lines of anti-estrogen therapy had significantly longer PFS than those who had received fewer therapeutic cycles (5 vs. 2 months); the degree of prior cytotoxic regimen exposure did not affect outcome.”

• cites [82] DeMichele, 2015, CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment, Clin Cancer Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Among paired tumor biopsies from 40 ribociclib patients, ≥50% reductions from baseline in Ki67 and phospho-pRB occurred in 55% and 42% of samples, respectively.

“Among paired tumor biopsies from 40 patients, reductions of ≥50% from baseline in Ki67 and phospho-pRB were documented in 55% and 42% of samples, respectively”

• cites [90] Infante, 2013, Abstract 276: phase 1 multicenter, open-label, dose-escalation study of LEE011, an oral inhibitor of cyclin-dependent kinase 4/6, in patients with advanced solid tumors or lymphomas, Mol Cancer Ther sourceNot checked yet

  Not checked in the free run.

• cites [91] Infante, 2014, A phase 1 study of the single-agent CDK4/6 inhibitor LEE011 in patients with advanced solid tumors and lymphomas, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Combination treatment was well tolerated overall, without increased incidence of febrile neutropenia.

“although combination treatment was well tolerated overall, even without increased incidence of febrile neutropenia”

May combine two claims.

Ribociclib plasma exposure increases were slightly higher than dose-proportional; mean half-life at 600 mg was 36.2 hours.

“Plasma exposure increases were slightly higher than dose-proportional; the mean half-life at the 600 mg dose level was 36.2 hrs.”

• cites [90] Infante, 2013, Abstract 276: phase 1 multicenter, open-label, dose-escalation study of LEE011, an oral inhibitor of cyclin-dependent kinase 4/6, in patients with advanced solid tumors or lymphomas, Mol Cancer Ther sourceNot checked yet

  Not checked in the free run.

• cites [91] Infante, 2014, A phase 1 study of the single-agent CDK4/6 inhibitor LEE011 in patients with advanced solid tumors and lymphomas, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

The quote only partly states this claim.

Palbociclib was provisionally approved by the FDA in early 2015 for ER+/HER2− breast cancer patients based on Phase 2 benefit.

“palbociclib was provisionally approved by the FDA in early 2015 for use in ER+/HER2− breast cancer patients”

May combine two claims.

Ribociclib and abemaciclib are orally bioavailable, highly selective CDK4/6 inhibitors with low nanomolar IC50 values, while other CDK family members are far less sensitive.

“Like palbociclib, these orally-bioavailable and highly selective CDK4/6-targeting agents exhibit IC50 values in the low nanomolar range, whereas other CDK family members are far less sensitive (1, 88, 89).”

• cites [1] Asghar, 2015, The history and future of targeting cyclin-dependent kinases in cancer therapy, Nat Rev Drug Discov sourceNot checked yet

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• cites [88] Gelbert, 2014, Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine, Invest New Drugs sourceNot checked yet

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• cites [89] Kim, 2013, Abstract PRO 2: LEE011: an orally bioavailable, selective small molecule inhibitor of CDK4/6 reactivating Rb in cancer, Mol Cancer Ther sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In abemaciclib Phase 1 expansion in advanced breast cancer, among 25 HR+/HER2− heavily pretreated patients, clinical benefit rate was 72%, including 7 partial responses (28%).

“among 25 patients with HR+/HER2− disease, the clinical benefit rate was 72%, including 7 partial responses (28%)”

• cites [92] Shapiro, 2013, A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

• cites [95] Patnaik, 2014, Abstract CT232: clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer, Cancer Res sourceNot checked yet

  Not checked in the free run.

• cites [96] Tolaney, 2015, Abstract P5-19-13: clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer, Cancer Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In the initial abemaciclib trial, the HR+/HER2+ group had 100% disease control rate with four partial responses, while three HR−/HER2+ patients had brief stable disease.

“The disease control rate in the HR+/HER2+ group was 100%, with four partial responses, whereas three patients with HR−/HER2+ disease had stable disease of brief duration (92, 95, 96).”

• cites [92] Shapiro, 2013, A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

• cites [95] Patnaik, 2014, Abstract CT232: clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer, Cancer Res sourceNot checked yet

  Not checked in the free run.

• cites [96] Tolaney, 2015, Abstract P5-19-13: clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer, Cancer Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Abemaciclib combined at full dose with fulvestrant in a small group had acceptable safety and promising efficacy.

“Abemaciclib has also been combined successfully at full dose with fulvestrant in a small group of patients, with acceptable safety and promising efficacy (96, 97)”

• cites [96] Tolaney, 2015, Abstract P5-19-13: clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer, Cancer Res sourceNot checked yet

  Not checked in the free run.

• cites [97] Patnaik, 2014, LY2835219, a novel cell cycle inhibitor selective for CDK4/6, in combination with fulvestrant for patients with hormone receptor positive (HR+) metastatic breast cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

For the entire HR+ population treated with abemaciclib, median duration of response was 13.4 months and median PFS was 8.8 months.

“for the entire HR+ population treated with abemaciclib, the median duration of response was 13.4 months and median PFS was 8.8 months.”

• cites [92] Shapiro, 2013, A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

• cites [95] Patnaik, 2014, Abstract CT232: clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer, Cancer Res sourceNot checked yet

  Not checked in the free run.

• cites [96] Tolaney, 2015, Abstract P5-19-13: clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer, Cancer Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Dose reductions for fatigue and diarrhea from 200 to 150 mg twice daily occurred, but 150 mg still produced pharmacodynamic CDK4/6 inhibition and was given continuously without interruption.

“Although dose reductions for fatigue and diarrhea from 200 to 150 mg twice daily occurred, 150 mg still produced pharmacodynamic CDK4/6 inhibition and was administered continuously without interruption”

• cites [92] Shapiro, 2013, A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

• cites [95] Patnaik, 2014, Abstract CT232: clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer, Cancer Res sourceNot checked yet

  Not checked in the free run.

• cites [96] Tolaney, 2015, Abstract P5-19-13: clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer, Cancer Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Genetic extinction of NRAS induces both apoptosis and cell-cycle arrest.

“In contrast, genetic extinction of NRAS induces both of these effects.”

• cites [109] Kwong, 2012, Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma, Nat Med sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Potent inhibitors of RAS-RAF-MEK-ERK signaling silence ERK phosphorylation, but interruption of feedback circuits can cause rebound ERK activity.

“although potent inhibitors of RAS-RAF-MEK-ERK signaling efficiently silence ERK phosphorylation, interruption of feedback circuits can result in rebound of ERK activity (110)”

• cites [110] Lito, 2012, Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas, Cancer Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The ribociclib-binimetinib combination had severe adverse effects, with dose-limiting toxicities including acute renal injury, elevated creatine phosphokinase, peripheral edema, and arrhythmia, likely due to binimetinib or the combination.

“The drug combination was not without severe adverse effects, with dose limiting toxicities including acute renal injury, elevated creatine phosphokinase, peripheral edema and arrhythmia most likely due to binimetinib or to consequences of combinatorial treatment.”

• cites [114] Sosman, 2014, A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: early encouraging clinical activity, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Among 17 GBM patients treated with abemaciclib, two had tumor size decrease and received treatment without progression for >16 months.

“Among 17 GBM patients, two patients had a decrease in tumor size and received treatment without progression for >16 months.”

• cites [92] Shapiro, 2013, A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In the abemaciclib NSCLC expansion, two partial responses occurred, including one KRAS mutant and one squamous NSCLC with CDKN2A copy number loss.

“Two partial responses were observed, including one patient with KRAS mutant NSCLC and one patient with squamous NSCLC and copy number loss of CDKN2A.”

• cites [92] Shapiro, 2013, A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

• cites [102] Goldman, 2014, Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with non-small cell lung cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In relapsed/refractory MCL, among 22 abemaciclib-treated patients, grade 3-4 neutropenia and thrombocytopenia occurred in about one-third, more common than in solid tumors.

“Among 22 patients, grade 3-4 neutropenia and thrombocytopenia were more common that in the solid tumor treatment setting, occurring in approximately one-third of patients.”

• cites [105] Morschhauser, 2014, Clinical activity of Abemaciclib (LY2835219), a cell cycle inhibitor selective for CDK4 and CDK6, in patients with relapsed refractory mantle cell lymphoma, Blood sourceNot checked yet

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May combine two claims.

In the abemaciclib NSCLC expansion, 31 (46%) patients had stable disease, including 15 on trial ≥6 months (four >12 months), for an overall disease control rate of 49% and 6-month PFS rate of 26%.

“Thirty-one (46%) patients had stable disease, including 15 patients who remained on trial ≥ 6 months (four of whom for > 12 months), for an overall disease control rate of 49% and 6 month PFS rate of 26%.”

• cites [92] Shapiro, 2013, A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

• cites [102] Goldman, 2014, Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with non-small cell lung cancer, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In a Phase 1 trial of ribociclib plus binimetinib in NRAS mutant melanoma, among 14 patients at the first two dose levels, six achieved partial response and six stable disease, including four with >20% tumor shrinkage.

“In a preliminary report of 14 patients receiving the first two dose levels, including ribociclib at 200 or 300 mg with binemetinib at 45 mg, six patients had achieved partial response and six had stable disease, including four with >20% tumor shrinkage.”

• cites [114] Sosman, 2014, A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: early encouraging clinical activity, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In the relapsed/refractory MCL abemaciclib trial, there were five partial responses and nine stable disease; among these 14, eight received ≥6 cycles.

“Overall, there were five partial responses and nine patients who achieved stable disease as the best response; among these 14 patients, eight received ≥ 6 cycles.”

• cites [105] Morschhauser, 2014, Clinical activity of Abemaciclib (LY2835219), a cell cycle inhibitor selective for CDK4 and CDK6, in patients with relapsed refractory mantle cell lymphoma, Blood sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Patients with HR+/HER2+ disease are likely to derive benefit from CDK4/6 inhibition, but whether activity is driven primarily by hormone receptor status and whether HR−/HER2+ patients benefit requires further work.

“Although patients with HR+/HER2+ disease are likely to derive benefit from CDK4/6 inhibition, further work will be required to determine if activity is driven primarily by the hormone receptor status and whether there is benefit for patients with HR−/HER2+ disease.”

May combine two claims.

CDK4 was identified as the critical driver of the differential phenotype; combined CDK4 and MEK inhibition led to apoptosis with blocked proliferation, net tumor regression, and substantial synergy.

“CDK4 was identified as the critical driver of this differential phenotype, so that combined inhibition of CDK4 and MEK led to apoptosis with blockade of continued proliferation, resulting in net tumor regression and substantial synergy in therapeutic efficacy.”

• cites [109] Kwong, 2012, Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma, Nat Med sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Combined CDK4/6 and PI3K or PI3K/mTOR signaling has been investigated preclinically primarily in breast cancer models, with the most promising results from PI3K α isoform-selective drugs.

“Combined CDK4/6 and PI3K or PI3K/mTOR signaling has been investigated preclinically primarily in models of breast cancer, where activation of the phosphoinositide 3-kinase (PI3K) pathway occurs frequently, with the most promising results emerging with PI3K α isoform-selective drugs.”

May combine two claims.

In sensitive cells and tumors responding to PI3K inhibition, RB phosphorylation is repressed; in less sensitive cells and non-responding tumors, RB phosphorylation is sustained.

“in sensitive cells, as well as in tumors from patients who responded to PI3K inhibition, there is repression of RB phosphorylation, whereas in cell lines with reduced sensitivity or in tumors from patients who did not respond to PI3K inhibition, RB phosphorylation is sustained.”

May combine two claims. The quote only partly states this claim.

Combined ribociclib-mediated CDK4/6 and PI3K inhibition synergistically reduces cell viability in vitro and leads to tumor regressions in vivo in PIK3CA mutant cell lines with modest PI3K inhibitor sensitivity.

“combined ribociclib-mediated CDK4/6 and PI3K inhibition synergistically reduces cell viability in vitro and leads to tumor regressions in vivo (115)”

• cites [115] Vora, 2014, CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors, Cancer Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Tumor regression in that trial was often early and accompanied by major symptomatic improvement.

“Tumor regression was often early and accompanied by major symptomatic improvement.”

• cites [114] Sosman, 2014, A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: early encouraging clinical activity, J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

MCLs express low levels of PIK31P1 compared to normal peripheral B cells; prolonged CDK4/6 inhibition induces PIK3IP1 expression and cooperates with PI3Kδ inhibition to cause robust apoptosis.

“MCLs express low levels of the negative PI3K regulator PIK31P1 compared to normal peripheral B cells; however, prolonged CDK4/6 inhibition has been shown to induce expression of PIK3IP1 in these cells and thereby cooperates with PI3Kδ inhibition to lead to robust apoptosis (123).”

• cites [123] Chiron, 2013, Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kdelta inhibition through PIK3IP1, Cell Cycle sourceNot checked yet

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May combine two claims.

Combined CDK4/6 and PI3Kδ inhibition may be effective after acquired ibrutinib resistance, and similar mechanisms may underlie synergy with BTK inhibition.

“Similar mechanistic considerations may underlie synergism of CDK4/6 inhibition with ibrutinib-mediated BTK inhibition; additionally, combined CDK4/6-PI3Kδ Inhibition may also be an effective strategy following the development of acquired ibrutinib resistance (124).”

• cites [124] Chiron, 2014, Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma, Cancer Discov sourceNot checked yet

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May combine two claims.

Sensitivity to combined CDK4/6 and IGF1R inhibition correlated with reduced mTORC1 activity, and combined CDK4/6 and temsirolimus recapitulated IGF1R combination effects.

“sensitivity to combined CDK4/6 and IGF1R inhibition correlated with reduced activity of mTORC1, and combined inhibition of CDK4/6 with temsirolimus recapitulated the effects of the IGF1R combination (120).”

• cites [120] Heilmann, 2014, CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers, Cancer Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Combined PI3K and CDK4/6 inhibition may be of interest in squamous NSCLC and head and neck cancer, where CCND1 and PIK3CA amplification are common, and in pancreatic cancer, where the PI3K pathway is downstream of activated KRAS.

“Combined PI3K and CDK4/6 inhibition may also be of substantial interest in squamous cell NSCLC and head and neck cancer, where amplification of both CCND1 and PIK3CA are common events (117, 118), as well as in pancreatic cancer, where genetically engineered mouse models have suggested the importance of the PI3K pathway downstream from activated KRAS (119).”

• cites [117] Schwaederle, 2015, Squamousness: next-generation sequencing reveals shared molecular features across squamous tumor types, Cell CycleNot checked yet

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• cites [118] TCGA, 2012, Comprehensive genomic characterization of squamous cell lung cancers, Nature sourceNot checked yet

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• cites [119] Eser, 2013, Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer, Cancer Cell sourceNot checked yet

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May combine two claims.

Some adaptations to CDK4/6 inhibition are reversible after drug removal, suggesting potential value of intermittent dosing schedules for maintaining cell cycle arrest.

“some of these adaptations are reversible after drug removal suggesting, perhaps counter-intuitively, the potential value of intermittent dosing schedules for maintenance of cell cycle arrest.”

• cites [108] Franco, 2014, CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer, Oncotarget sourceNot checked yet

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• cites [134] Wang, 2007, Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia, Blood sourceNot checked yet

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• cites [135] Dean, 2010, Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure, Oncogene sourceNot checked yet

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• cites [136] Zhang, 2014, Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo, Mol Cancer Ther sourceNot checked yet

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May combine two claims.

Many tumors lacking p16INK4a or overexpressing D-type cyclins are exquisitely sensitive to CDK4/6 inhibitors, whereas many normal cells are relatively resistant, implying cancer cells become addicted to RB pathway mutations.

“Many tumors lacking p16INK4a or overexpressing D-type cyclins have shown exquisite sensitivity to CDK4/6 inhibitors, whereas many normal cells are relatively resistant, implying that cancer cells become “addicted” to RB pathway mutations (132).”

• cites [132] Weinstein, 2008, Relevance of the concept of oncogene addiction to hormonal carcinogenesis and molecular targeting in cancer prevention and therapy, Adv Exp Med Biol sourceNot checked yet

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May combine two claims.

In MCL models, idelelasib monotherapy achieves transient AKT phosphorylation inhibition but only modest effects on cell proliferation.

“where idelelasib (Zydelig ™) monotherapy achieves transient inhibition of AKT phosphorylation but only modest effects on cell proliferation.”

• cites [123] Chiron, 2013, Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kdelta inhibition through PIK3IP1, Cell Cycle sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Recent results in pancreatic patient-derived xenografts suggest CDK4/6 inhibition alone may be highly effective in suppressing proliferation, raising the question of whether established cell lines are adequate for assessing therapeutic sensitivities.

“recent results in pancreatic patient-derived xenografts suggest that CDK4/6 inhibition alone may be highly effective in suppressing proliferation, raising the question of whether established cell lines are adequate for assessing therapeutic sensitivities (121).”

• cites [121] Witkiewicz, 2015, Selective impact of CDK4/6 suppression on patient-derived models of pancreatic cancer, Oncotarget sourceNot checked yet

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May combine two claims.

Computational models predicted that the observed synergy of CDK4 and IGF1R inhibitors depends on activated AKT; combined inhibition cooperatively suppressed AKT pathway protein activation.

“The models predicted that the observed synergy of CDK4 and IGF1R inhibitors depends on activated AKT; consistent with this prediction, combined inhibition of CDK4 and IGF1R cooperatively suppressed activation of proteins within the AKT pathway (122).”

• cites [122] Miller, 2013, Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets, Sci Signal sourceNot checked yet

  Not checked in the free run.

May combine two claims.

CDK4/6 inhibitors induce G1 phase arrest in tumors with functional RB, so they may blunt the effects of cytotoxic drugs or ionizing irradiation that kill in S- or M-phase.

“Because CDK4/6 inhibitors induce G1 phase arrest in tumors expressing functional RB, they may well blunt the effects of cytotoxic drugs or ionizing irradiation (IR), which kill cancer cells in S- or M-phase (2).”

• cites [2] VanArsdale, 2015, Molecular pathways: targeting the cyclin D-CDK4/6 axis for cancer treatment, Clin Cancer Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In a mouse RB-competent MMTV-HER2-driven breast cancer model, palbociclib compromised carboplatin anti-tumor activity, whereas in an RB-deficient model, palbociclib protected against carboplatin-induced hematologic toxicity.

“in a mouse RB-competent MMTV-HER2-driven breast cancer model, the anti-tumor activity of carboplatin was compromised by palbociclib administration, whereas in an RB-deficient model, palbociclib co-administration protected against carboplatin-induced hematologic toxicity (129).”

• cites [129] Roberts, 2012, Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy, J Natl Cancer Inst sourceNot checked yet

  Not checked in the free run.

May combine two claims.

p16INK4A-deficient pancreatic cancer cell lines may be inherently resistant to CDK4/6 inhibitors; synergistic compromise of proliferation and viability has been shown with PI3K inhibitors and IGF1R inhibitors in vitro and in vivo.

“p16INK4A-deficient pancreatic cancer cell lines may be inherently resistant to CDK4/6 inhibitors; synergistic compromise of cell proliferation and viability have been demonstrated with PI3K inhibitors (108), as well as with inhibitors of IGF1R both in vitro and in vivo (120).”

• cites [108] Franco, 2014, CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer, Oncotarget sourceNot checked yet

  Not checked in the free run.

• cites [120] Heilmann, 2014, CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers, Cancer Res sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

Additional drugs targeting mitogenic signaling pathways in RB-positive tumors may convert cytostatic responses to durable cell cycle arrest or cell death.

“Additional drugs targeting mitogenic signaling pathways in RB-positive tumors may be able to convert cytostatic responses to durable cell cycle arrest (senescence) or cell death (apoptosis).”