Mechanisms of Resistance to CDK4/6 Inhibitors in Breast Cancer and Potential Biomarkers of Response

Guarducci, Cristina; Bonechi, Martina; Boccalini, Giulia; Benelli, Matteo; Risi, Emanuela; Leo, Angelo Di; Malorni, Luca; Migliaccio, Ilenia

doi:10.1159/000484167

Cited by 55 publications

(40 citation statements)

References 44 publications

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“…Its downregulation is described in various tumors, most frequently through promoter methylation, and results in deregulation of cycle and proliferation (16,17). Interestingly, CCNE1 overexpression and loss of CDK inhibitor p21 have been reported as mechanisms of resistance to palbociclib in breast cancer (18).…”

Section: Discussionmentioning

confidence: 99%

Activity and Safety of Palbociclib in Patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Biomarker-driven Phase II Study

Toulmonde

Blay

Bouché

et al. 2019

Clinical Cancer Research

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Purpose: CDKN2A loss is frequent in gastrointestinal stromal tumors (GISTs) and associated with aggressive outcome. Palbociclib is a CDK4 inhibitor with preclinical antitumor efficacy in tumors with P16/CDKN2A loss. Patients and Methods: This is a multicenter single-arm phase II clinical trial assessing safety and efficacy of palbociclib in patients with advanced GIST bearing CDKN2A gene loss. Adults with unresectable locally advanced or metastatic, refractory to at least imatinib and sunitinib, measurable and documented progressive disease (PD) as per RECIST 1.1, and CDKN2A deletion centrally assessed were eligible. Patients received palbociclib 125 mg orally daily on a 21 days on/7 days off dosing schedule, until PD or unacceptable toxicity. The primary endpoint was 4-month non-PD rate according to RECIST 1.1. Results: As of May 2017, 71 patients had been included in the study, and 29 patients (40.3%) met the molecular eligibility requirement. Twenty-five patients (86.2%) had grade 1-2 adverse events (AEs) and 12 patients (41.4%) grade 3-4 AEs possibly related to the drug. The planned interim statistical analysis performed after central histologic and radiological review showed that 19 (86.4%) out of the first 22 evaluable patients had PD at 4 months. CDKN2A status had no impact either on overall survival or outcome on previous standard lines of treatment. Translational analysis suggested upregulation of CCNE1 or downregulation of CDKN1A/P21 or LRRC3B as potential mechanisms of resistance. Conclusions: Palbociclib has no significant clinical activity as a single agent in P16/CDKN2A-deleted GIST refractory to imatinib and sunitinib.

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Section: Discussionmentioning

confidence: 99%

Activity and Safety of Palbociclib in Patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Biomarker-driven Phase II Study

Toulmonde

Blay

Bouché

et al. 2019

Clinical Cancer Research

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“…As the primary target of CDK4/6 inhibitors, RB was considered to be one of the most important biomarkers of sensitivity to therapy. [24][25][26] In this scenario, loss of RB is the evident cause of resistance to CDK4/6 inhibitors, 24 and various preclinical studies have supported this hypothesis. 20,27,28 In addition, some preclinical and clinical studies have also reported that mutations in RB are responsible for the resistance.…”

Section: Cell Cycle-specific Mechanismsmentioning

confidence: 96%

“…The tumor suppressor RB is the aforementioned key checkpoint in the cell cycle. As the primary target of CDK4/6 inhibitors, RB was considered to be one of the most important biomarkers of sensitivity to therapy . In this scenario, loss of RB is the evident cause of resistance to CDK4/6 inhibitors, and various preclinical studies have supported this hypothesis .…”

Section: Mechanisms Of Resistance To Cdk4/6 Inhibitorsmentioning

confidence: 99%

Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review

Pandey

Kim

et al. 2019

Intl Journal of Cancer

224

188

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Deregulation of the cyclin D‐CDK4/6‐INK4‐RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle‐specific mechanisms and cell cycle‐nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well.

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“…Deregulation of the Rb pathway and the expression of cyclin E1 (CCNE1) have been described as mediators of response to CDK4/6 inhibitors (21,28,29). Therefore, we analyzed the mRNA expression of RB1 and CCNE1, as well as a gene expression signature of Rb loss-of- (18,25,27).…”

Section: Response By Baseline Clinical Pathologic and Molecular Chamentioning

confidence: 99%

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer

Hurvitz

Martín

Press

et al. 2020

Clinical Cancer Research

136

114

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Purpose: neoMONARCH assessed the biological effects of abemaciclib in combination with anastrozole in the neoadjuvant setting. Patients and Methods: Postmenopausal women with stage I-IIIB HR þ /HER2 À breast cancer were randomized to a 2-week lead-in of abemaciclib, anastrozole, or abemaciclib plus anastrozole followed by 14 weeks of the combination. The primary objective evaluated change in Ki67 from baseline to 2 weeks of treatment. Additional objectives included clinical, radiologic, and pathologic responses, safety, as well as gene expression changes related to cell proliferation and immune response. Results: Abemaciclib, alone or in combination with anastrozole, achieved a significant decrease in Ki67 expression and led to potent cell-cycle arrest after 2 weeks of treatment compared with anastrozole alone. More patients in the abemaciclib-containing arms versus anastrozole alone achieved complete cell-cycle arrest (58%/68% vs. 14%, P < 0.001). At the end of treatment, following 2 weeks lead-in and 14 weeks of combination therapy, 46% of intent-to-treat patients achieved a radiologic response, with pathologic complete response observed in 4%. The most common all-grade adverse events were diarrhea (62%), constipation (44%), and nausea (42%). Abemaciclib, anastrozole, and the combination inhibited cell-cycle processes and estrogen signaling; however, combination therapy resulted in increased cytokine signaling and adaptive immune response indicative of enhanced antigen presentation and activated T-cell phenotypes. Conclusions: Abemaciclib plus anastrozole demonstrated biological and clinical activity with generally manageable toxicities in patients with HR þ /HER2 À early breast cancer. Abemaciclib led to potent cell-cycle arrest, and in combination with anastrozole, enhanced immune activation.

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Mechanisms of Resistance to CDK4/6 Inhibitors in Breast Cancer and Potential Biomarkers of Response

Cited by 55 publications

References 44 publications

Activity and Safety of Palbociclib in Patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Biomarker-driven Phase II Study

Activity and Safety of Palbociclib in Patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Biomarker-driven Phase II Study

Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer

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