Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer

Sobhani, Navid; D’Angelo, Alberto; Pittacolo, Matteo; Roviello, Giandomenico; Otto, Tobias

doi:10.20944/preprints201902.0245.v1

Cited by 44 publications

(25 citation statements)

References 73 publications

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“…The cyclin-dependent kinases regulating cell-cycle progression have been considered as promising targets for breast cancer therapy because they were shown to contribute to the development of resistance to ET [ 4 , 16 ]. Palbociclib was the first third-generation and highly-selective oral CDK4/6 inhibitor discovered that demonstrated a substantially improved PFS for HR + /HER2 - breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Palbociclib, together with the others CDK4/6 inhibitors ribociclib and abemaciclib, received FDA and EMA approval for the treatment of HR + /HER2 - mBC in combination with either AIs or fulvestrant based on the PALOMA-2, MONALEESA 2 and the MONARCH 2 randomized clinical trials, respectively [ 12 , 15 , 17 , 18 ]. These studies demonstrated significant improvements in PFS and tolerable safety profiles [ 4 ]. For palbociclib, the pivotal registration trials PALOMA-2 and PALOMA-3 evaluated its efficacy and safety in combination with letrozole and fulvestrant in first- and second-line settings, respectively [ 11 , 12 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Despite the effectivity of ET, it is often associated with the appearance of acquired resistance after exposure to one or more lines of treatment [ 2 ]. Some resistance is driven from alterations of the cell cycle due to upregulation of the cyclin pathway [ 3 , 4 ]. Palbociclib is a small molecule with highly specific and selective inhibitory activity against CDK4 and CDK6, and its therapeutic potential for HR + /HER2 - mBC has been extensively studied in the last decade [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP)

et al. 2020

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Background This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR + /HER2 - ) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. Patients and methods Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR + /HER2 - mBC who had progressed on ≥4 treatments for advanced disease were eligible. Results A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7–7.0) and the median overall survival was 19.0 months (95% CI 16.4–21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37–2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia. Conclusions Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP)

et al. 2020

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“…Recently, a combination of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6)—palbociclib, ribociclib, and abemaciclib—with aromatase inhibitors or the ER inhibitor fulvestrant resulted in a markedly improved progression-free survival (PFS) compared to endocrine therapy alone in patients with advanced ER + breast cancer [ 5 ]. Even though the majority of patients with advanced disease treated with CDK4/6 inhibitors and antiestrogens benefit from this combination, virtually all patients eventually display disease progression, underscoring the need to discover mechanisms of resistance to this new standard of care.…”

Section: Introductionmentioning

confidence: 99%

Targeting Aberrant FGFR Signaling to Overcome CDK4/6 Inhibitor Resistance in Breast Cancer

Sobhani

Fassl

Mondani

et al. 2021

Cells

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Breast cancer (BC) is the most common cause of cancer-related death in women worldwide. Therapies targeting molecular pathways altered in BC had significantly enhanced treatment options for BC over the last decades, which ultimately improved the lives of millions of women worldwide. Among various molecular pathways accruing substantial interest for the development of targeted therapies are cyclin-dependent kinases (CDKs)—in particular, the two closely related members CDK4 and CDK6. CDK4/6 inhibitors indirectly trigger the dephosphorylation of retinoblastoma tumor suppressor protein by blocking CDK4/6, thereby blocking the cell cycle transition from the G1 to S phase. Although the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib gained FDA approval for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative BC as they significantly improved progression-free survival (PFS) in randomized clinical trials, regrettably, some patients showed resistance to these therapies. Though multiple molecular pathways could be mechanistically responsible for CDK4/6 inhibitor therapy resistance, one of the most predominant ones seems to be the fibroblast growth factor receptor (FGFR) pathway. FGFRs are involved in many aspects of cancer formation, such as cell proliferation, differentiation, and growth. Importantly, FGFRs are frequently mutated in BC, and their overexpression and/or hyperactivation correlates with CDK4/6 inhibitor resistance and shortened PFS in BC. Intriguingly, the inhibition of aberrant FGFR activity is capable of reversing the resistance to CDK4/6 inhibitors. This review summarizes the molecular background of FGFR signaling and discusses the role of aberrant FGFR signaling during cancer development in general and during the development of CDK4/6 inhibitor resistance in BC in particular, together with other possible mechanisms for resistance to CDK4/6 inhibitors. Subsequently, future directions on novel therapeutic strategies targeting FGFR signaling to overcome such resistance during BC treatment will be further debated.

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“…Cyclin-dependent kinase (CDK) 4/6 inhibitors in combination with endocrine therapy had been approved by the US Food and Drug Administration as a first-or second-line treatment of HR-positive/ HER2-negative breast cancer [ 3 ]. CDK4/6 inhibitors prevent retinoblastoma (RB) protein phosphorylation and eventually restrict G1 to S phase cell progression [ 4 ]. Despite evidence of clinical benefit, concerns regarding CDK4/6 inhibitor resistance have been emerging [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Deregulated Immune Pathway Associated with Palbociclib Resistance in Preclinical Breast Cancer Models: Integrative Genomics and Transcriptomics

Pandey

Lee

Park

et al. 2021

Genes

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Recently, cyclin-dependent kinase (CDK) 4/6 inhibitors have been widely used to treat advanced hormone receptor-positive breast cancer. Despite promising clinical outcomes, almost all patients eventually acquire resistance to CDK4/6 inhibitors. Here, we screened genes associated with palbociclib resistance through genomics and transcriptomics in preclinical breast cancer models. Palbociclib-resistant cells were generated by exposing hormone receptor-positive breast cancer cell lines to palbociclib. Whole-exome sequencing (WES) and a mRNA microarray were performed to compare the genomic and transcriptomic landscape between both palbociclib-sensitive and resistant cells. Microarray analysis revealed 651 differentially expressed genes (DEGs), while WES revealed 107 clinically significant mutated genes. Furthermore, pathway analysis of both DEGs and mutated genes revealed immune pathway deregulation in palbociclib-resistant cells. Notably, DEG annotation revealed activation of type I interferon pathway, activation of immune checkpoint inhibitory pathway, and suppression of immune checkpoint stimulatory pathway in palbociclib-resistant cells. Moreover, mutations in NCOR1, MUC4, and MUC16 genes found in palbociclib-resistant cells were annotated to be related to the immune pathway. In conclusion, our genomics and transcriptomics analysis using preclinical model, revealed that deregulated immune pathway is an additional mechanism of CDK4/6 inhibitor resistance besides the activation of cyclin E-CDK2 pathway and loss of RB, etc. Further studies are warranted to evaluate whether immune pathways may be a therapeutic target to overcome CDK4/6 inhibitor resistance.

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Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer

Cited by 44 publications

References 73 publications

Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP)

Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP)

Targeting Aberrant FGFR Signaling to Overcome CDK4/6 Inhibitor Resistance in Breast Cancer

Deregulated Immune Pathway Associated with Palbociclib Resistance in Preclinical Breast Cancer Models: Integrative Genomics and Transcriptomics

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