Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors

Goel, Shom; Wang, Qi; Watt, April C.; Tolaney, Sara M.; Dillon, Deborah; Li, Wei; Ramm, Susanne; Palmer, Adam C.; Yuzugullu, Haluk; Varadan, Vinay; Tuck, David; Harris, Lyndsay N.; Wong, Kwok-Kin; Liu, X. Shirley; Siciński, Piotr; Winer, Eric P.; Krop, Ian E.; Zhao, Jean J.

doi:10.1016/j.ccell.2016.02.006

Cited by 384 publications

(450 citation statements)

References 30 publications

(35 reference statements)

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“…1 ). Preclinical data suggested that CDK4/6 inhibitors would be active in HER2 -amplifi ed breast cancer ( 10 ). In this study, Patnaik and colleagues showed that 4 of 11 patients (36%) with HER2-positive disease achieved objective antitumor responses to abemaciclib ( 4 ), supporting ongoing clinical studies of combination regimens with anti-HER2 agents (NCT02448420, NCT01976169, and NCT02657343).…”

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confidence: 52%

CDK4/6 Inhibitors: Promising Opportunities beyond Breast Cancer

2016

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Summary: Patnaik and colleagues report on the safety, pharmacokinetics, pharmacodynamics, and preliminary effi cacy of abemaciclib for the treatment of advanced solid cancers, demonstrating antitumor activity in advanced breast cancers as well as glioblastoma, melanoma, non-small cell lung cancer, colorectal cancer, and ovarian cancer. The development of abemaciclib and other CDK4/6 inhibitors should now be fully optimized through the use of novel predictive biomarkers of response and rational combinations. Cancer Discov; 6(7); 697-9. ©2016 AACR.See related article by Patnaik et al., p. 740 (4).It is now more than two decades since the critical roles of D-type cyclins (CCND) and cyclin-dependent kinases (CDK) in the cell cycle were established. Although the inhibition of these targets to halt G 1 -S phase progression is a rational therapeutic strategy, a delicate balance needs to be struck between optimal target blockade to induce cell death in tumor cells and the relative sparing of CDK activity in nonmalignant cells. Early efforts to target CDK in the clinic had been largely unsuccessful due to toxicity, but next-generation CDK inhibitors have created a therapeutic window with improved selectivity for CDK4 and CDK6 ( 1 ). The three selective CDK4/6 inhibitors, abemaciclib, palbociclib, and ribociclib, all in late-stage clinical development, are structurally similar, bind within the ATP-binding pocket of CDK4 and CDK6, and have high selectivity for CDK4/6 over CDK1/2. In 2015, palbociclib was the fi rst CDK4/6 inhibitor to obtain FDA accelerated approval for the fi rst-line treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in combination with letrozole (PALOMA-1; ref. 2 ), before subsequently gaining full FDA approval with fulvestrant in metastatic breast cancer after progression on initial endocrine therapy ref. 3 ).In this issue, Patnaik and colleagues report data from the phase I trial of abemaciclib, which led in part to the FDA breakthrough therapy designation for refractory hormone receptor-positive (HR + ) advanced breast cancer ( 4 ). This study comprised a two-stage phase I trial design with dose escalation and expansion cohorts conducted in multiple a priori -determined tumor-specifi c groups. The authors should be commended on a comprehensive and well-conducted phase I trial where key hypothesis-testing questions involving drug pharmacology, antitumor activity, and putative predictive biomarkers of response and resistance were tested. This phase I biomarker-driven trial design, supported by robust and biologically rational preclinical data to identify the tumor and molecular subtypes likely to benefi t ( 5 ), may accelerate the development of promising new agents by enabling early clinical testing of enriched tumor-selected and molecularly selected patients, so as to generate suffi cient data to support expedited regulatory approval.The authors established the recommended phase II dose (RP2D) at 200...

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confidence: 52%

CDK4/6 Inhibitors: Promising Opportunities beyond Breast Cancer

2016

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“…Cyclin D1-CDK4 inactivates the tuberous sclerosis complex 2 (TSC2) by phosphorylation, relieving its inhibitory activity on mTORC1; mTORC1 can then exert its feedback inhibition of upstream HER receptors [Chandarlapaty et al 2011]. Inhibition of CDK4/6 then restores HER receptors' activity, resensitizing tumors to HER2 blockade [Goel et al 2016].…”

Section: Cyclin-dependent Kinase 4/6 Inhibitors: Preclinical Activitymentioning

confidence: 99%

“…Tumors progressing after anti-HER2 therapy often show cyclin D1 overexpression, and abemaciclib has shown activity against anti-HER2-resistant tumors in mouse models, synergizing with anti-HER2 therapies and restoring sensitivity to anti-HER2 drugs [Goel et al 2016]. Cyclin D1-CDK4 inactivates the tuberous sclerosis complex 2 (TSC2) by phosphorylation, relieving its inhibitory activity on mTORC1; mTORC1 can then exert its feedback inhibition of upstream HER receptors [Chandarlapaty et al 2011].…”

Section: Cyclin-dependent Kinase 4/6 Inhibitors: Preclinical Activitymentioning

confidence: 99%

Progress with palbociclib in breast cancer: latest evidence and clinical considerations

et al. 2016

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Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HRpositive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer.

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“…As one example of this, we recently demonstrated a non-canonical pathway through which CDK4/6 inhibitors can be utilized to overcome resistance to other targeted therapies [6]. Our research has focused on resistance to anti-HER2 targeted therapies in breast cancers with amplification of the ERBB2 oncogene (which encodes for the HER2 receptor tyrosine kinase).…”

Section: Editorialmentioning

confidence: 99%

“…Combination therapy leads to more potent shutdown of mTOR activity and the combined mTOR/RB suppression enhances therapeutic effect. (Modified from Goel et al, Cancer Cell 2016 [6]) levels (e.g. those that increase cyclin D transcription through the Ras-Raf-Mek-Erk pathway or cyclin D stability through the PI3K-AKT pathway) [5]; and (ii) those which might show increased dependency on CDK4/6 due to cyclin D gene amplification, loss of p16 INK4a , or unique chromosomal rearrangements increasing cyclin D expression.…”

Section: Editorialmentioning

confidence: 99%

CDK4/6 inhibition: the late harvest cycle begins

Goel

Zhao

2016

Oncotarget

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Effective and safe pharmacologic inhibition of the cyclin dependent kinases (CDKs) has been a goal of cancer researchers for many years. CDKs are attractive therapeutic targets in cancer for two main reasons -first, some tumors harbor dependencies on particular CDKs for their initiation and maintained growth; second, there is a surprising amount of redundancy between various CDKs in maintaining normal organ function [1,2]. These observations suggest that it might be possible to inhibit a certain CDK to slow tumor growth without invoking prohibitive toxicity. Unfortunately, clinical trials using CDK inhibitors have largely failed due to low potency and specificity of the agents used.Recently, however, medicinal chemists have developed a new generation of more potent and selective CDK inhibitors. Of these, inhibitors of CDK4 and CDK6 ("CDK4/6 inhibitors") are the best characterized and have progressed furthest in clinical development. Indeed, recent trials have shown that the addition of palbociclib (a potent and selective CDK4/CDK6 inhibitor) to endocrine therapy significantly improves progression-free survival in women with advanced hormone receptor-positive breast cancer, leading to its accelerated approval by the FDA in 2015 [3]. This success has sparked enthusiasm for CDK4/6 inhibitors and a large number of trials testing CDK4/6 inhibition for a variety of tumor types have opened. Agents in development include palbociclib, abemaciclib, and ribociclib.The canonical function of CDKs 4 and 6 is to facilitate cellular transition from G1 to S phase of the cell cycle. This is achieved when levels of a D-type cyclin (cyclin D1, D2, or D3) rise in G1, facilitating formation of a cyclin D-CDK4/6 holoenzyme (also incorporating a Cip/Kip subunit such as p21 or p27) [4]. The active kinase phosphorylates the retinoblastoma tumor suppressor protein (RB), liberating RB from E2F family transcription factors. This promotes expression of genes regulating the G1-S transition. It is not surprising, therefore, that pharmacologic CDK4/6 inhibitors suppress RB phosphorylation, induce G1 arrest, and ultimately produce a senescent-like phenotype in sensitive tumor cells. Indeed, these effects alone are likely to render these agents as effective therapies for many tumors.Understanding these canonical CDK4/6 pathways might allow us to rapidly identify tumors that are likely to be sensitive to pharmacologic inhibition of these kinases. Potential candidates include: (i) tumors driven by oncogenes that are known to increase cyclin D protein EditorialFigure 1: Exploiting a non-canonical CDK4/6 pathway to overcome drug resistance. A non-canonical function of CDK4/6 that can be exploited for therapeutic benefit. Left: In a drug-resistant HER2-positive breast cancer cell, CDK4 phosphorylates RB and also interacts with TSC2. CDK4 activity enhances mTOR activity, leading to feedback suppression of upstream receptor tyrosine kinases (RTKs). Middle: When the cell is treated with a CDK4/6 inhibitor (red arrows), RB phosphorylation declines, suppre...

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Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors

Cited by 384 publications

References 30 publications

CDK4/6 Inhibitors: Promising Opportunities beyond Breast Cancer

CDK4/6 Inhibitors: Promising Opportunities beyond Breast Cancer

Progress with palbociclib in breast cancer: latest evidence and clinical considerations

CDK4/6 inhibition: the late harvest cycle begins

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