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Future Med Chem. 2015 August; 7(12): 1473–1481.
PMCID: PMC4625900
NIHMSID: NIHMS724766

New directions for drug-resistant breast cancer: the CDK4/6 inhibitors

Abstract

Many breast cancers are treated with selective estrogen receptor modulators (SERMs) if the cancers are estrogen and progesterone hormone receptor positive. However, some 30% are not responsive or later become resistant to such therapies. There has been continued interest in developing new and more effective SERMs that target the estrogen receptors for therapeutic benefit. This article will focus on therapies directed against other molecular targets to improve outcomes, as preventing growth of breast cancer cells by an unrelated mechanism is most likely to yield success against resistance, or synergize in a combination therapy with SERMs or aromatase inhibitors. New drugs in development that target the cyclin-dependent kinases CDK4/CDK6 have ‘breakthrough therapy’ designation at the US FDA and may provide an exciting and realistic new avenue to patients in the near future.

Selective estrogen receptor modulators & hormone-responsive (receptor positive) breast cancers

At diagnosis, breast cancers are tested for the presence of hormone receptors, estrogen receptors (ERs) and progesterone receptors (PRs). Presence of both is a positive indication that the cancer will be treatable and responsive to antihormone therapies that inhibit ER function. These drugs are more specifically referred to as selective estrogen receptor modulators (SERMs) as they have estrogen activity in some tissues while they can block estrogen action in other tissues. For example, many SERMs will help to maintain bone mineral density while inhibiting the growth of breast cancer cells. SERMs act by binding to the ERs (ER-α and ER-β) in the estrogen hormone-binding pocket and inducing a protein conformation that is less effective at interacting with coactivators that amplify transcription of estrogen-regulated genes. These gene products can lead to growth stimulation of cells by producing autocrine and paracrine growth factors and other mitogenic signals.

Over the previous decade, a major clinical trial, the STAR trial, compared the use of tamoxifen (first-generation SERM) versus raloxifene (a second-generation SERM) for breast cancer therapy and chemoprevention [1]. Raloxifene was originally approved by the US FDA to prevent osteoporosis, for which its use remains most common. The results of the STAR trial indicated that raloxifene compared favorably to tamoxifen, causing less uterine cancers and fewer potentially fatal thromboembolic events, while still being effective for prevention and therapy against breast cancer.

One of the most recently approved SERMs is lasofoxifene, approved in Europe but not the USA, for osteoporosis prevention. This third-generation SERM was also studied in a large clinical trial, the PEARL trial, which compared several outcomes, almost all favorable relative to placebo [2]. It is marketed in Europe for bone maintenance, but it also has been shown to prevent breast cancers [3]. It may have some potential benefit for a subset of tamoxifen-resistant cancers. However, there are no markers or clinical features that predict responsiveness to one particular SERM over another in ER+ breast cancer patients.

Another group of compounds can bind within the hormone binding pocket of the ERs and result in a higher turnover rate of the ER protein, removing it from the cell, and are hence referred to as selective estrogen receptor degraders (SERDs). Only one has been approved by the FDA for clinical use as a breast cancer therapy, fulvestrant (Faslodex; ICI 182,780) [4]. However its oral bioavailability is limited, so it requires delivery by injection. There are additional compounds that have some SERD activity, including bazedoxifene, though it is being investigated for osteoporosis prevention and relief of menopausal symptoms [2]. Further approaches by pharmaceutical companies have included development of SERMs paired with conjugated estrogens, such as those found in Premarin, for safer and effective menopausal symptom relief (tissue selective estrogen complex; bazedoxifene plus conjugated estrogens) without the need for a progestogen to prevent endometrial cancer [2].

There are likely limitations to SERM usage clinically against tamoxifen-resistant cancers due to their similar mechanism of action and no clear measure of when to use one or another of the newer, alternative SERMs. Development of further SERMs for breast cancer therapy and resistance may have other more pragmatic limitations. Since there are already approved and effective SERMs used clinically for prevention and therapy of breast cancer and for osteoporosis, the major drug companies appear to be unlikely to allocate the resources for further FDA approvals and diminishing economic returns [3].

Aromatase inhibitors

Another class of molecules used in clinical therapies to inhibit the actions of ERs for breast cancer prevention and treatment includes the aromatase inhibitors (AIs). These block the CYP450 aromatase enzyme that converts androgens to estrogens, the major source of estrogens in postmenopausal women, thereby diminishing local and systemic estrogen concentrations. AIs are already well established in the clinic and have exhibited positive benefit [4,5].

Three AIs have been approved for use by the FDA. Letrozole and anastrozole are competitive inhibitors of CYP19 aromatase and provide longer disease-free periods after breast cancer than tamoxifen [5]. Exemestane (a steroidal AI) is a noncompetitive, irreversible substrate of CYP19 aromatase. A large clinical trial compared a SERM, tamoxifen versus an AI, anastrozole (ATAC trial). These clinical data are important with regard to development of therapies against SERM-resistant cancers. Use of the antibody trastuzumab (Herceptin) against HER2+ tumors has also proven valuable, after tamoxifen is no longer effective in advanced ER-, HER2+ tumors.

Currently for late-stage advanced breast cancer, aggressive, DNA-damaging or microtubule disrupting chemotherapy is used to treat hormone-resistant breast cancers. These treatments are associated with significant clinical side effects and diminished quality of life for the patient and have only limited efficacy. Clearly there is an urgent need for better targeted therapies as an alternative to chemotherapy for these resistant tumors.

A new direction with particular promise: the cell cycle inhibitors

Targeting the ERs and estrogen action has been a successful method for prevention and treatment of breast cancer for decades. However, there are cancers that do not respond or become resistant to SERMs, so targeting other molecules and pathways may offer new and synergistic benefits.

The cell cycle checkpoint may present such a target. Cell division proceeds through a highly regulated series of steps to result in two daughter cells [6]. Most cells in the body are in a quiescent phase, referred to as G0, where cell division activities are not present.

Cells can become activated by growth factors or other mitogenic signals to enter the G1 phase, where the cell grows larger in size, accumulates proteins, ribosomes and organelles and prepares for S phase, when highly organized DNA replication occurs (Figure 1). G2 follows with continued cell growth and preparation for mitosis, the actual division of the cell with chromosomes and organelles appropriately allocated to both daughter cells. The G1, S and G2 phase are collectively referred to as interphase, while the nongrowing M phase consists of mitotic cell division.

Figure 1.
The four phases of the cell cycle.

There are checkpoints at each of the key commitment steps to proceed through the cell cycle. These checkpoints act as a control to make sure each phase of the cell cycle has been faithfully completed before moving to the next phase. In cancers, these steps and controlling proteins are often deregulated and continuously moving forward, leading to uncontrolled cell proliferation and tumorigenesis [6].

Though it has been two decades since the first proposals to inhibit key molecules controlling the cell cycle, the lack of eventual clinical benefit in humans has hindered successful application for cancer patients [6,8]. One long-studied goal is the selective interruption of cell cycle regulation in cancer cells by interfering with serine/threonine cyclin-dependent kinase (CDK) action, causing the cancer cells to die, with minimal toxicity to normal cells [6].

The early cell cycle inhibiting drugs included flavopiridol and CY-202, which are pan-inhibitors, targeting many of the CDKs. Flavopiridol inhibits CDK1, CDK2, CDK4, CDK5, CDK7 and CDK9, while CY-202 inhibits all but CDK4 [9]. Neither of these agents was particularly successful in the clinic, where the effects must be primarily limited to cancer cells without high toxicity to normal cells. A number of second generation cyclin-dependent kinase inhibitors (CKIs) have now been developed that are either high affinity pan-CDK inhibitors or have selectivity to a specific subset of the CDKs.

It appears through knockout, gene ablation experiments in mice that not all CDKs are necessary for development and growth of every cell type. For many, the loss of a single CDK can be compensated by other activities, while for some CDKs in specific cell types, a particular CDK is required. For example, cdk2 null mice are viable, but sterile, due to a meiotic cell division defect in germ cells [9]. Deletion of cdk4 shows defects in adult pancreatic β cells and pituitary endocrine cells, while cdk6 loss results in reduced erythroid cell numbers. However, the fact that many of the functions can be compensated by other CDKs results in a less severe toxicity profile in normal cells, with targeted inhibition of specific CDKs [9].

Inhibition of certain CDKs may provide protection against oncogenic processes in specific tissue types. For example, CDK4 is not required for normal mammary tissue development based on knockout mouse studies, but it is needed for growth of Ras-induced mammary tumors, suggesting a potential therapeutic window for treatment with lower toxicity [10].

Recently, there have been exciting developments for drugs targeting specific CDKs. The CDK4/CDK6 inhibitors have been given the ‘breakthrough drug designation’ in April 2013 by the FDA in an effort to streamline development and approval for use in patients.

The role of CDKs (CDK4/6)

One of the key checkpoints in the cell cycle is the first one, a rate-limiting transition from G1 to S phase, committing the cell to divide by initiating the events leading to DNA replication. Cells that do not pass this point, the restriction point, will cease cell division and enter the quiescent stage, G0.

With growth factor or other mitogenic stimulation, increased expression of the short-lived cyclin D protein will reach sufficient concentrations to complex individually with CDK4 or CDK6 proteins to activate those kinases and phosphorylate target proteins. CDK4 and CDK6 are inactive unless each has been bound by a cyclin D regulator protein. Some of the notable kinase targets are retinoblastoma protein (Rb) and closely related p107 and p130, tumor suppressor proteins that allow the cell cycle to proceed to S phase after they are phosphorylated (pRb) (Figure 2) [11]. Unphosphorylated Rb is bound to a transcription factor E2F and prevents its transcriptional activity at target genes. Once released from pRb, E2F drives expression of a number of genes, including those whose products are involved in nucleotide metabolism and DNA synthesis, and including Cyclin E, which will bind and activate CDK2 to further phosphorylate Rb, generate more E2F and move the cell through the G1-S transition to DNA replication [11]. Often in cancers, genetic alterations can increase the activities of CDK4/6, for example, by overexpressing cyclin D, leading to a higher number of active CDK4/6 kinases, Rb phosphorylation, release of E2F, progression to S phase and cell division. Cyclin D protein is often found at increased levels in breast cancers and some melanomas as a result of upstream activating mutations of PIK3CA and BRAF kinases, respectively. Gene amplifications can also lead to increased cyclin D proteins, and other mutations can reduce the expression of inhibitors such as p15, p16, p18 (INK4 proteins) that normally inhibit cell cycling by binding directly to CDK4 and blocking cyclin D binding.

Figure 2.
E2F dynamics at the restriction point.

Palbociclib (PD-0332991; Pfizer): a specific CDK4/CDK6 inhibitor

In April 2013, the FDA granted breakthrough therapy designation to Pfizer for the experimental breast cancer drug, palbociclib (PD-0332991), an oral inhibitor of CDK4/6 kinases, providing hope that it may soon reach the market. Breakthrough therapy designation can be applied to single or combination therapies that may exhibit substantial improvement over current standard of care for a serious or life-threatening disease, and this designation will help to speed the development and review of the drug.

In preclinical studies, palbociclib was shown to be an inhibitor of cell growth and a suppressor of DNA replication by preventing cells from entering S phase [13,14], and clinical trial results have been very promising. Early results from a Phase II study presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium showed that the drug had blocked disease progression in 165 patients for more than 2 years [15]. Most of the trial patients had aggressive breast cancer, either metastatic disease or a short disease-free interval following adjuvant therapy. ER positive tumors were the best predictive marker for this response to the CDK4/6 inhibitor.

The FDA's Breakthrough Therapy designation was based on the Phase II trial and interim data (PALOMA-1) that showed that women with advanced breast cancer who were treated with the combination of palbociclib and letrozole (an aromatase inhibitor) exhibited a much longer progression-free survival period (26.1 months) than patients who received only letrozole (7.5 months) [15,16].

For postmenopausal patients with advanced or metastatic breast cancer, approximately 60% of cases are ER+, HER2-, markers of tumors for which palbociclib appears to be most effective [17]. ER positivity appears to correlate well with a functional Rb pathway, required for the effectiveness of CDK4/6 kinase inhibitors that prevent Rb phosphorylation [8,11]. Rb is defective or missing in approximately 10% of cancers, so those patients would not be appropriate candidates for treatment with these drugs [16]. With currently available therapies in the clinic, survival rates for advanced or metastatic breast cancer continue to be disappointing.

Pfizer announced in February 2014 that the randomized Phase II efficacy trial (PALOMA-1) of palbociclib achieved its primary endpoint. It demonstrated a statistically significant and clinically meaningful improvement in progression-free survival for the combination of palbociclib and letrozole compared with letrozole alone in postmenopausal women with ER+, HER2- locally advanced or newly diagnosed metastatic breast cancer [17].

Pfizer has started and continues to enroll patients in a randomized, double-blind, multicenter Phase III clinical trial, PALOMA-2 (study 1008) to test palbociclib in combination with letrozole versus letrozole alone as a first-line treatment for postmenopausal patients with ER+, HER2- locally advanced or metastatic breast cancer (Table 1) [18]. PALOMA-3 (study 1023) is another Phase III clinical trial that evaluates palbociclib in combination with fulvestrant (a SERD) versus fulvestrant plus placebo in women with ER+, HER2- metastatic breast cancer whose disease has progressed after prior endocrine therapy – that is, SERM resistance [19].

Table 1.
Selected current clinical trials for the specific CDK4/6 inhibitors.

The CDK4/6 inhibitors block cells from progressing through the cell cycle rather than inducing DNA replication errors and mutations that hope to kill rapidly growing cells, the aim of most chemotherapies, so these opposing drug classes should not be used simultaneously.

LEE011 (Novartis): a highly selective CDK4/6 inhibitor

There are also new CDK4/6 inhibitor drugs in development by Novartis and Eli Lilly. Novartis has already completed Phase I studies of LEE011, an orally bioavailable, highly selective small molecule inhibitor of CDK4/6 kinases with inhibitory IC50 concentrations in the low nanomolar range. As it is highly selective for these targets, it remains to be seen if it eventually becomes a best in class drug for its indications.

Results for the Novartis drug LEE011 were presented in October 2013 at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, in Boston, MA [46]. LEE011 was reported to be a most selective CDK4/6 inhibitor and to have dose dependent antitumor activity in a number of preclinical models. LEE011 inhibited growth of tumor cells by arresting the cells, as expected, at the G1 checkpoint described above, which prevents the cells from proliferating.

Novartis has multiple Phase I safety trials in adult cancers, and a Phase I trial in pediatric cancers [47]. Clinical data show LEE011 is well tolerated with excellent pharmacokinetic properties. Investigators are testing LEE011 in Phase I clinical trials in adults as a single agent for cancers that are dependent on CDK4/6, including liposarcomas, mantle cell lymphomas and head and neck cancers. In the ongoing Phase I study on pediatric cancers, LEE011 is being tested as a single agent in neuroblastoma and malignant rhabdoid tumors [47,48].

LEE011 showed positive results in drug-resistant breast cancers and melanomas when tested in combination with other targeted therapies. As CDK4/6 kinases act downstream of a number of oncogenic driver mutations, LEE011 was shown to have positive results in ER+ breast cancers that also had activating mutations of PIK3CA kinases and in melanomas with activating changes in BRAF or NRAS. In vivo experiments showed that because cyclin D is an upregulated target of BRAF and PIK3CA kinases, LEE011 was effective as a single agent in mice bearing melanomas with BRAF mutations, and those bearing breast cancers with PIK3CA mutations [46].

When LEE011 was paired with LGX818, a BRAF-specific inhibitor, it exhibited strong antitumor activity against melanomas that were either sensitive or resistant to LGX818 [48]. Likewise if LEE011 was combined with a PIK3CA specific inhibitor, BYL719, it also showed strong antitumor activity in BYL719 sensitive or resistant breast cancer models [48]. It also appeared to prevent resistance to those drugs that otherwise would have developed with the single agent use. A number of clinical studies of LEE011 as a single agent and in combinations are currently underway (Table 1) [46].

Novartis announced that LEE011 will be used in Phase III trials that will eventually enroll up to 500 women with advanced or resistant breast cancers. It was started in December 2013, to be completed in 2016 [48,31]. This foreshadows eventual direct competition with Pfizer's drug, studied for late-stage ER+/HER2- advanced breast cancer.

Eli Lilly is developing LY2835219, a CDK4/6 inhibitor

LY2835219 has been shown in vitro to be a selective ATP-competitive inhibitor of CDK4/6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation [49,50]. LY2835219 inhibits the kinases with an IC50 value of 2 nM for CDK4 and 10 nM for CDK6. This orally available drug is currently in Phase I safety trials, designated NCT01394016 (Table 1) [45], and has shown acceptable safety and clinical activity as a single agent. It is also able to cross the blood–brain barrier for potential therapies there [49,50].

Conclusion & future perspective

Many human tumors exhibit gene mutations that directly activate CDK4/6. This, or loss of the tumor suppressor protein retinoblastoma (Rb), results in increased proliferation rates by decreasing dependency on external growth factors to proceed through the G1/S checkpoint. The CDK4/6 inhibitors block phosphorylation of Rb, preventing the cell cycle progression to S Phase and DNA replication, thereby blocking cell proliferation. As CDK4/6 inhibitors target a different mechanism of action, they are proposed as a combination therapy with SERMs or AIs to avoid resistance in the first place, or to treat SERM and drug-resistant cancers, and advanced metastatic ER+, HER2- breast cancers.

The CDK4/6 inhibitors block cells from progressing through the cell cycle rather than inducing DNA replication errors and mutations that hope to kill rapidly growing cells, the aim of most chemotherapies, so these opposing drug classes should not be used simultaneously. Palbociclib received Breakthrough Therapy designation by the FDA in 2013 for treatment of women with advanced or metastatic ER+, HER2- breast cancer. It was given accelerated approval by the FDA in February 2015 (named Ibrance) for use with letrozole for that group of patients as a first-line therapy.

The CDK4/6 inhibitors, palbociclib from Pfizer, Ribociclib from Novartis, and Abemaciclib from Lilly, show much promise to complement and improve on other therapies in use for advanced breast cancers. Competition to have the most efficacious drug is intense and should produce better options for patients in less than 2 years. This class of molecules is likely to be used in combination therapies for a number of cancer types over the next 5–10 years, becoming part of the future standard of care.

Key terms

Selective estrogen receptor modulators (SERMs): Compounds that can activate estrogen receptors and signaling in some tissues (e.g., bone), while inhibiting it in others (e.g., breast).

Cell cycle checkpoint: A control mechanism to insure that the processes at each phase of the cell cycle have been accurately completed before committing to progression to the next phase.

Cyclin-dependent kinases (CDKs): Serine/threonine kinases that are activated when bound to their partner cyclin protein to phosphorylate target proteins, leading to progression of the cell cycle toward producing two daughter cells.

Cyclin-dependent kinase inhibitor (CKI): A CKI can block the ATP site of the CDK kinase that would normally donate the phosphate group to the targeted substrate, thus inhibiting the reaction. A CKI can also be a protein that interacts with a cyclin-CDK complex to block kinase activity, usually during G1 or in response to signals from the environment or from damaged DNA.

Executive summary

  • The CDK4/6 inhibitors block phosphorylation of the tumor suppressor protein, Rb. This prevents the cell cycle progression to DNA replication in S phase, thereby blocking cell proliferation.
  • Many human tumors exhibit gene mutations that directly activate CDK4/6, by gene amplification or kinase signaling that increases expression of protein activators like cyclin D, or by genetic losses that reduce protein inhibitors like p16. These mechanisms, or loss of retinoblastoma (Rb), result in increased proliferation rates by decreasing dependency on external growth factors and mitogenic signaling pathways to proceed through the G1/S checkpoint.
  • These CDK4/6 inhibitors block cells from progressing through the cell cycle rather than inducing DNA replication errors and mutations that hope to kill rapidly growing cells, the aim of most chemotherapies, so these opposing drug classes should not be used simultaneously.
  • Because the CDK4/6 inhibitors target a different mechanism of action than SERMs, they are proposed as a combination therapy with SERMs or AIs to avoid resistance in the first place, or to treat SERM and drug-resistant cancers, and advanced metastatic ER+, HER2- breast cancers.
  • Palbociclib received Breakthrough Therapy designation by the US FDA in April 2013, for the initial treatment studies of women with advanced or metastatic ER+, HER2- breast cancer. This designation was based on data from the Phase II PALOMA-1 trial. Two randomized Phase III trials (PALOMA-2 and PALOMA-3) are enrolling such patients and may lead to FDA approval, combining palbociclib with either letrozole or fulvestrant for first-line therapy.
  • The CDK4/6 inhibitors, palbociclib (Ibrance) from Pfizer, Ribociclib from Novartis and Abemaciclib from Lilly, show much promise to complement and improve on other therapies already in use for advanced breast cancers, among others. Competition to be first to market with an efficacious drug is intense and should produce better options for patients within 2 years.

Footnotes

Financial & competing interests disclosure

The author has received funding from the NIH grants CA87414 and DK59516. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

References

1. Vogel VG. Update on raloxifene: role in reducing the risk of invasive breast cancer in postmenopausal women. Breast Cancer. 2011;3:127–137. [PMC free article] [PubMed]
2. Pinkerton JV, Thomas S. Use of SERMs for treatment in postmenopausal women. J. Steroid Biochem. Mol. Biol. 2014;142:142–154. [PubMed]
3. Schmidt C. Third-generation SERMs may face uphill battle. J. Natl Cancer Inst. 2010;102(22):1690–1692. [PubMed]
4. Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N. Engl. J. Med. 2012;367(5):435–444. [PMC free article] [PubMed]
5. Van Asten K, Neven P, Lintermans A, et al. Aromatase inhibitors in the breast cancer clinic: focus on exemestane. Endocr. Relat. Cancer. 2014;21(1):R31–R49. [PubMed]
6. Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat. Rev. Drug Discov. 2009;8(7):547–566. [PubMed]
7. Wikipedia. Overview on the eukaryotic cell cycle and the regulatory cyclin/CDK complexes. http://upload.wikimedia.org/wikipedia/commons/6/68/Bun%C4%9B%C4%8Dn%C3%BD_cyklus_CDK.svg
8. Węsierska-Gądek J, Maurer M, Zulehner N, Komina O. Whether to target single or multiple CDKs for therapy? That is the question. J. Cell Physiol. 2011;226(2):341–349. [PubMed]
9. Malumbres M, Pevarello P, Barbacid M, Bischoff JR. CDK inhibitors in cancer therapy: what is next? Trends Pharmacol. Sci. 2008;29(1):16–21. [PubMed]
10. Yu Q, Sicinska E, Geng Y, et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell. 2006;9(1):23–32. [PubMed]
11. Dean JL, Thangavel C, McClendon AK, et al. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene. 2010;29(28):4018–4032. [PubMed]
12. Holsberger DR, Cooke PS. Understanding the role of thyroid hormone in Sertoli cell development: a mechanistic hypothesis. Cell Tissue Res. 2005;322(1):133–140. [PubMed]
13. Finn RS, Dering J, Conklin D, et al. 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. 2009;11(5):R77. [PMC free article] [PubMed]
14. Logan JE, Mostofizadeh N, Desai AJ, et al. PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity. Anticancer Res. 2013;33(8):2997–3004. [PubMed]
15. Finn R. 2012 San Antonio Breast Cancer Symposium (SABCS) San Antonio; Texas, USA: 2012. Results of a randomized Phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (BC) Presented at. Abstract S1–S6.
16. CDK inhibitor triples PFS in breast cancer. Cancer Discovery. 2013;3:4.
17. Pfizer announces positive top-line results from PALOMA-1 evaluating palbociclib plus letrozole in women with advanced breast cancer clinical benefit demonstrated for potential first-in-class CDK 4 and 6 Inhibitor. www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_positive_top_line_results_from_paloma_1_evaluating_palbociclib_plus_letrozole_in_women_with_advanced_breast_cancer
18. http://clinicaltrials.gov/ct2/show/NCT01740427 ClinicalTrials Database: NCT01740427.
19. https://clinicaltrials.gov/ct2/show/NCT01942135 ClinicalTrials Database: NCT01942135.
20. https://clinicaltrials.gov/ct2/show/NCT02028507 ClinicalTrials Database: NCT02028507.
21. https://clinicaltrials.gov/ct2/show/NCT01864746 ClinicalTrials Database: NCT01864746.
22. https://clinicaltrials.gov/ct2/show/NCT01709370 ClinicalTrials Database: NCT01709370.
23. https://clinicaltrials.gov/ct2/show/NCT01723774 ClinicalTrials Database: NCT01723774.
24. https://clinicaltrials.gov/ct2/show/NCT01976169 ClinicalTrials Database: NCT01976169.
25. https://clinicaltrials.gov/ct2/show/NCT02022982 ClinicalTrials Database: NCT02022982.
26. https://clinicaltrials.gov/ct2/show/NCT01320592 ClinicalTrials Database: NCT01320592.
27. https://clinicaltrials.gov/ct2/show/NCT01536743 ClinicalTrials Database: NCT01536743.
28. https://clinicaltrials.gov/ct2/show/NCT01356628 ClinicalTrials Database: NCT01356628.
29. https://clinicaltrials.gov/ct2/show/NCT01522989 ClinicalTrials Database: NCT01522989.
30. https://clinicaltrials.gov/ct2/show/NCT01111188 ClinicalTrials Database: NCT01111188.
31. http://clinicaltrials.gov/ct2/show/NCT01958021 ClinicalTrials Database: NCT01958021.
32. https://clinicaltrials.gov/ct2/show/NCT02278120 ClinicalTrials Database: NCT02278120.
33. https://clinicaltrials.gov/ct2/show/NCT02422615 ClinicalTrials Database: NCT02422615.
34. https://clinicaltrials.gov/ct2/show/NCT01857193 ClinicalTrials Database: NCT01857193.
35. https://clinicaltrials.gov/ct2/show/NCT01919229 ClinicalTrials Database: NCT01919229.
36. https://clinicaltrials.gov/ct2/show/NCT01872260 ClinicalTrials Database: NCT01872260.
37. https://clinicaltrials.gov/ct2/show/NCT01777776 ClinicalTrials Database: NCT01777776.
38. https://clinicaltrials.gov/ct2/show/NCT02088684 ClinicalTrials Database: NCT02088684.
39. https://clinicaltrials.gov/ct2/show/NCT02246621 ClinicalTrials Database: NCT02246621.
40. https://clinicaltrials.gov/ct2/show/NCT02107703 ClinicalTrials Database: NCT02107703.
41. https://clinicaltrials.gov/ct2/show/NCT01739309 ClinicalTrials Database: NCT01739309.
42. https://clinicaltrials.gov/ct2/show/NCT02102490 ClinicalTrials Database: NCT02102490.
43. https://clinicaltrials.gov/ct2/show/NCT02057133 ClinicalTrials Database: NCT02057133.
44. https://clinicaltrials.gov/ct2/show/NCT02014129 ClinicalTrials Database: NCT02014129.
45. http://clinicaltrials.gov/ct2/show/NCT01394016 ClinicalTrials Database: NCT01394016.
46. Kim S, Loo A, Chopra R, et al. LEE011: an orally bioavailable, selective small molecule inhibitor of CDK4/6– reactivating Rb in cancer. AACR; Mol. Cancer Ther. 2013;12(11 Suppl.) Abstract PR02.
47. Rader J, Russell MR, Hart LS, et al. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin. Cancer Res. 2013;19(22):6173–6182. [PMC free article] [PubMed]
48. Samson K. LEE011 CDK inhibitor showing early promise in drug-resistant cancers. Oncology Times. 2014;36(3):39–40.
49. Shapiro G, Rosen LS, Tolcher AW, et al. A first-in-human Phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer. J. Clin. Oncol. 2013;31(Suppl.) Abstract 2500.
50. Gelbert LM, Cai S, Lin X, et al. Identification and characterization of LY2835219: a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) with broad in vivo antitumor activity. Mol. Cancer Ther. 2011;10(11 Suppl.) Abstract B233.

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