Distinct Mechanisms of Resistance to CDK4/6 Inhibitors Require Specific Subsequent Treatment Strategies: One Size Does Not Fit All.
Cancer research
Cyclin-dependent kinase (CDK) 4/6 inhibitors have transformed the treatment landscape of patients with hormone receptor-positive breast cancers. However, despite improvements in clinical outcomes, the approximately 70% of patients with tumors that are not intrinsically resistant to a CDK4/6 inhibitor still ultimately acquire resistance, which leads to a dilemma for clinicians when deciding which treatment to offer patients when they demonstrate disease progression on a CDK4/6 inhibitor. As such, many groups have sought to understand the mechanisms of resistance to CDK4/6 inhibitors, mostly focusing on genetic alterations associated with resistance. Though several recurrent mutations have been described, they are not consistent enough to guide clinical practice or generate novel rational treatment options. Two recent publications have used transcriptomic analysis to unravel distinct mechanisms driving resistance to individual CDK4/6 inhibitors and in doing so have identified biomarkers that could potentially help identify the next course of treatment for patients following disease progression.
10.1158/0008-5472.CAN-23-2608
Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future.
Spring Laura M,Wander Seth A,Andre Fabrice,Moy Beverly,Turner Nicholas C,Bardia Aditya
Lancet (London, England)
The development and approval of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer represents a major milestone in cancer therapeutics. Three different oral CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have significantly improved progression-free survival by a number of months when combined with endocrine therapy. More recently, improvement in overall survival has been reported with ribociclib and abemaciclib. The toxicity profile of all three drugs is well described and generally easily manageable with dose reductions when indicated. More myelotoxicity is observed with palbociclib and ribociclib, but more gastrointestinal toxicity is observed with abemaciclib. Emerging data is shedding light on the resistance mechanisms associated with CDK4/6 inhibitors, including cell cycle alterations and activation of upstream tyrosine kinase receptors. A number of clinical trials are exploring several important questions regarding treatment sequencing, combinatorial strategies, and the use of CDK4/6 inhibitors in the adjuvant and neoadjuvant settings, thereby further expanding and refining the clinical application of CDK4/6 inhibitors for patients with breast cancer.
10.1016/S0140-6736(20)30165-3
ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer.
Breast cancer research : BCR
In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to the backbone of therapy, estrogen deprivation by aromatase inhibition. How these mutations affect tumor sensitivity to established and novel therapies are active areas of research. These therapies include estrogen receptor-targeting agents, such as selective estrogen receptor modulators, covalent antagonists, and degraders (including tamoxifen, fulvestrant, and novel agents), and combination therapies, such as endocrine therapy plus CDK4/6, PI3K, or mTORC1 inhibition. In this review, we summarize existing knowledge surrounding the mechanisms of action of ESR1 mutations and roles in resistance to aromatase inhibition. We then analyze the recent literature on how ESR1 mutations affect outcomes in estrogen receptor-targeting and combination therapies. For estrogen receptor-targeting therapies such as tamoxifen and fulvestrant, ESR1 mutations cause relative resistance in vitro but do not clearly lead to resistance in patients, making novel agents in this category promising. Regarding combination therapies, ESR1 mutations nullify any aromatase inhibitor component of the combination. Thus, combinations using endocrine alternatives to aromatase inhibition, or combinations where the non-endocrine component is efficacious as monotherapy, are still effective against ESR1 mutations. These results emphasize the importance of investigating combinatorial resistance, challenging as these efforts are. We also discuss future directions and open questions, such as studying the differences among distinct ESR1 mutations, asking how to adjust clinical decisions based on molecular surveillance testing, and developing novel therapies that are effective against ESR1 mutations.
10.1186/s13058-021-01462-3
CDK4 and CDK6 kinases: From basic science to cancer therapy.
Science (New York, N.Y.)
Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) and their activating partners, D-type cyclins, link the extracellular environment with the core cell cycle machinery. Constitutive activation of cyclin D–CDK4/6 represents the driving force of tumorigenesis in several cancer types. Small-molecule inhibitors of CDK4/6 have been used with great success in the treatment of hormone receptor–positive breast cancers and are in clinical trials for many other tumor types. Unexpectedly, recent work indicates that inhibition of CDK4/6 affects a wide range of cellular functions such as tumor cell metabolism and antitumor immunity. We discuss how recent advances in understanding CDK4/6 biology are opening new avenues for the future use of cyclin D–CDK4/6 inhibitors in cancer treatment.
10.1126/science.abc1495
Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor.
Freeman-Cook Kevin,Hoffman Robert L,Miller Nichol,Almaden Jonathan,Chionis John,Zhang Qin,Eisele Koleen,Liu Chaoting,Zhang Cathy,Huser Nanni,Nguyen Lisa,Costa-Jones Cinthia,Niessen Sherry,Carelli Jordan,Lapek John,Weinrich Scott L,Wei Ping,McMillan Elizabeth,Wilson Elizabeth,Wang Tim S,McTigue Michele,Ferre Rose Ann,He You-Ai,Ninkovic Sacha,Behenna Douglas,Tran Khanh T,Sutton Scott,Nagata Asako,Ornelas Martha A,Kephart Susan E,Zehnder Luke R,Murray Brion,Xu Meirong,Solowiej James E,Visswanathan Ravi,Boras Britton,Looper David,Lee Nathan,Bienkowska Jadwiga R,Zhu Zhou,Kan Zhengyan,Ding Ying,Mu Xinmeng Jasmine,Oderup Cecilia,Salek-Ardakani Shahram,White Michael A,VanArsdale Todd,Dann Stephen G
Cancer cell
The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR/HER2 breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.
10.1016/j.ccell.2021.08.009
Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer.
Formisano Luigi,Lu Yao,Servetto Alberto,Hanker Ariella B,Jansen Valerie M,Bauer Joshua A,Sudhan Dhivya R,Guerrero-Zotano Angel L,Croessmann Sarah,Guo Yan,Ericsson Paula Gonzalez,Lee Kyung-Min,Nixon Mellissa J,Schwarz Luis J,Sanders Melinda E,Dugger Teresa C,Cruz Marcelo Rocha,Behdad Amir,Cristofanilli Massimo,Bardia Aditya,O'Shaughnessy Joyce,Nagy Rebecca J,Lanman Richard B,Solovieff Nadia,He Wei,Miller Michelle,Su Fei,Shyr Yu,Mayer Ingrid A,Balko Justin M,Arteaga Carlos L
Nature communications
Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.
10.1038/s41467-019-09068-2
Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition.
Álvarez-Fernández Mónica,Malumbres Marcos
Cancer cell
Inhibiting the cell-cycle kinases CDK4 and CDK6 results in significant therapeutic effect in patients with advanced hormone-positive breast cancer. The efficacy of this strategy is, however, limited by innate or acquired resistance mechanisms and its application to other tumor types is still uncertain. Here, through an integrative analysis of sensitivity and resistance mechanisms, we discuss the use of CDK4/6 inhibitors in combination with available targeted therapies, immunotherapy, or classical chemotherapy with the aim of improving future therapeutic uses of CDK4/6 inhibition in a variety of cancers.
10.1016/j.ccell.2020.03.010