CDK 4/6 Inhibitor Palbociclib (PD0332991) in Rb+ Advanced Breast Cancer: Phase II Activity, Safety, and Predictive Biomarker Assessment

DeMichele, Angela; Clark, Amy S.; Tan, Kay See; Heitjan, Daniel F.; Gramlich, Kristi; Gallagher, Maryann; Lal, Priti; Feldman, Michael D.; Zhang, Paul; Colameco, Christopher; Lewis, David; Langer, Melissa; Goodman, Noah; Domchek, Susan M.; Gogineni, Keerthi; Rosen, Mark; Fox, Kevin R.; O’Dwyer, Peter J.

doi:10.1158/1078-0432.ccr-14-2258

Cited by 300 publications

(293 citation statements)

References 26 publications

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“…In contexts where deregulation of Cyclin D:Cdk4/6 kinases drives tumorigenesis, inhibition of these kinases can trigger cellular senescence or apoptosis (Fry et al 2004;Thangavel et al 2011;Choi et al 2012;Sawai et al 2012). Cdk4/6 inhibitors had modest effects when tested as a monotherapy in solid tumors (Flaherty et al 2012;Dickson et al 2013;Cadoo et al 2014;DeMichele et al 2015;Vaughn et al 2015). This may reflect the fact that many signaling pathways converge on CDK regulation, and cells can express alternative CDKs that phosphorylate similar or overlapping sets of substrates.…”

Section: The Translation Of Rb Researchmentioning

confidence: 99%

RB1: a prototype tumor suppressor and an enigma

2016

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The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?

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Section: The Translation Of Rb Researchmentioning

confidence: 99%

RB1: a prototype tumor suppressor and an enigma

2016

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“…Much recent excitement has been generated by trials demonstrating the anticancer efficacy of CDK4/6-selective inhibitors in both preclinical studies and in a subset of patients in clinical trials (Michaud et al, 2010;Leonard et al, 2012;Dickson et al, 2013;DeMichele et al, 2015;Vora et al, 2014;Young et al, 2014). These agents appear to be particularly effective when combined with the aromatase inhibitor letrozole in patients with estrogen receptor-positive breast cancer (Finn et al, 2015).…”

Section: Cdk4/6-selective Compoundsmentioning

confidence: 99%

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics

et al. 2015

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Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATPcompetitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non-ATPcompetitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non-ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer.

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“…However, the earlier class of CDK inhibitors had limited specificity, inadequate clinical activity, poor pharmacokinetic properties, and unacceptable toxicity profiles (10,11,14,15). These disappointing initial efforts now have been followed by the development of the specific CDK4/6 inhibitors palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219), which have demonstrated manageable toxicities, improved pharmacokinetic properties, and impressive antitumor activity, especially in certain forms of breast cancer (14,16). Successful early clinical trials with these three CDK4/6 inhibitors have generated cautious enthusiasm that these drugs may emerge as a new class of anticancer agents (14,17).…”

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confidence: 99%

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

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Gibson

Buege

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a rapid decline in kidney function caused by ischemic or toxic injury to renal tubular cells. The widely used chemotherapy drug cisplatin accumulates preferentially in the renal tubular cells and is a frequent cause of drug-induced AKI. During the development of AKI the quiescent tubular cells reenter the cell cycle. Strategies that block cell-cycle progression ameliorate kidney injury, possibly by averting cell division in the presence of extensive DNA damage. However, the early signaling events that lead to cell-cycle activation during AKI are not known. In the current study, using mouse models of cisplatin nephrotoxicity, we show that the G1/S-regulating cyclin-dependent kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell-cycle entry but before the development of AKI. Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival. Of additional significance, these compounds were found to be potent inhibitors of organic cation transporter 2 (OCT2), which contributes to the cellular accumulation of cisplatin and subsequent kidney injury. The unique cell-cycle and OCT2-targeting activities of palbociclib and LEE011, combined with their potential for clinical translation, support their further exploration as therapeutic candidates for prevention of AKI.

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CDK 4/6 Inhibitor Palbociclib (PD0332991) in Rb+ Advanced Breast Cancer: Phase II Activity, Safety, and Predictive Biomarker Assessment

Cited by 300 publications

References 26 publications

RB1: a prototype tumor suppressor and an enigma

RB1: a prototype tumor suppressor and an enigma

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

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