CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives

Roberto, Michela; Astone, A.; Botticelli, Andrea; Carbognin, Luisa; Cassano, Alessandra; D’Auria, G.; Fabbri, Agnese; Fabi, Alessandra; Gamucci, Teresa; Krasniqi, Eriseld; Minelli, Mauro; Orlandi, Armando; Pantano, Francesco; Paris, Ida; Pizzuti, Laura; Portarena, Ilaria; Salesi, Nello; Scagnoli, Simone; Scavina, Paola; Tonini, Giuseppe; Vici, Patrizia; Marchetti, Paolo

doi:10.3390/cancers13020332

Cited by 43 publications

(36 citation statements)

References 66 publications

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“…3e,f ), consistent with their complementary effects on blocking ER+ cancer cell growth driven by activation of ER and subsequent CDK4/6 cell cycle proteins. This drug synergy is consistent with the clinical effect of the combination in patients, which shows remarkable efficacy in metastatic ER+ breast cancer (56, 57). As our third line of evidence, resistant cells also facilitate sensitive cells when treated with ER antagonists in coculture, perhaps due to overcoming the antagonism with additional estradiol as with ribociclib treatment ( Fig.…”

Section: Discussionsupporting

confidence: 83%

Ecological interactions in breast cancer: Cell facilitation promotes growth and survival under drug pressure

Emond

Griffiths

Grolmusz

et al. 2021

Preprint

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Competition between different lineages of cells within a tumor has been considered in cancer evolution and progression, but positive interactions like facilitation have received far less study. We developed isogenic estrogen positive breast cancer cell lineages (CAMA-1 and MCF7) sensitive and resistant to CDK4/6 inhibition in order to investigate the mechanisms of cell interaction under selective pressure. When these sensitive and resistant lineages are grown in coculture under ribociclib treatment, sensitive cells survive and proliferate better than in monoculture despite the effects of competition. Conditioned media taken from resistant CAMA-1 cells reproduces this advantage, suggesting that secretion of some factor from resistant cells underlies the effect. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays were used to identify factors secreted by cell lineages. While the less active estrone metabolite was detected in medium from both lineages, highly active estradiol was only detectable in media that included resistant cells. Because sensitive cells are more dependent on estrogen signaling than resistant cells, they benefit from the increase in local estradiol, leading to facilitated growth when in coculture in the presence of ribociclib. This facilitation of sensitive cells by resistant cells is recapitulated when cells are treated with small molecule inhibitors that target estrogen signaling pathways. We developed a set of mathematical models to quantify the strength of competition and facilitation between cell lines and evaluate the effects of treatments that modify these interactions. These analyses support the conclusion that resistant cell lineages benefit sensitive lineages during therapy through the increased production and sharing of local estradiol, and themselves suffer from increased competition and suppression as a result. Our multidisciplinary approach analyzes and quantifies interactions between ER+ cancer lineages during treatment and provides the framework to evaluate these effects in patients and improve therapy.

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Section: Discussionsupporting

confidence: 83%

Ecological interactions in breast cancer: Cell facilitation promotes growth and survival under drug pressure

Emond

Griffiths

Grolmusz

et al. 2021

Preprint

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“…With the development of treatment and detection technologies, many other potential therapeutic targets have been found among patients with CDK4/6 inhibitor resistance (Figure 1). 36,73 A better understanding of the mechanism of CDK4/6 inhibitor resistance may improve the rational selection of next-line therapy. 37,38 Loss of retinoblastoma protein (RB), p16 amplification, CCNE1 overexpression, fibroblast growth factor receptor 1 (FGFR1) amplification, mitotic Aurora kinase (AURKA) amplification, E2F amplification, and cyclin-dependent kinase 2 (CDK2) overexpression have all been reported to be associated with CDK4/6 inhibitor resistance.…”

Section: Other Targetsmentioning

confidence: 99%

“…37,38 Loss of retinoblastoma protein (RB), p16 amplification, CCNE1 overexpression, fibroblast growth factor receptor 1 (FGFR1) amplification, mitotic Aurora kinase (AURKA) amplification, E2F amplification, and cyclin-dependent kinase 2 (CDK2) overexpression have all been reported to be associated with CDK4/6 inhibitor resistance. [73][74][75][76][77][78][79][80][81][82][83] We can use tissue or liquid biopsies to identify potential therapeutic targets in patients with CDK4/6 inhibitor resistance and provide individualized therapy based on the results. 73 For example, if ESR1 mutation is found, we can use SERD drugs such as fulvestrant or elacestrant to deal with the ESR1 mutation.…”

Section: Other Targetsmentioning

confidence: 99%

“…[73][74][75][76][77][78][79][80][81][82][83] We can use tissue or liquid biopsies to identify potential therapeutic targets in patients with CDK4/6 inhibitor resistance and provide individualized therapy based on the results. 73 For example, if ESR1 mutation is found, we can use SERD drugs such as fulvestrant or elacestrant to deal with the ESR1 mutation. 84,85 For patients with FGFR1 amplification, AURKA amplification, or CDK2 overexpression, FGFR1 inhibitors, AURKA inhibitors, and CDK2 inhibitors, respectively, could be used to treat patients who developed resistance during CDK4/6 inhibitor use.…”

Section: Other Targetsmentioning

confidence: 99%

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Advances in Therapy for Hormone Receptor (HR)-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced Breast Cancer Patients Who Have Experienced Progression After Treatment with CDK4/6 Inhibitors

Li¹,

Li²

2021

OTT

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Approximately 70% of breast cancer (BC) cases are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) BC. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have acted as star drugs for reversing endocrine therapy (ET) resistance and improving the prognosis of patients with HR+ advanced breast cancer (ABC) since they were initially approved. However, progression eventually occurs. In this review, we summarize the recent treatment strategies post CDK4/6 inhibitors: 1) CDK4/6 inhibitors plus exemestane and everolimus; 2) phosphoinositide-3-kinase (PI3K) inhibitor alpelisib plus fulvestrant for patients with PIK3CA mutation; 3) poly (ADP-ribose) polymerase (PARP) inhibitor for patients with germline PALB2 mutations, somatic BRCA1/2 mutations, or germline BRCA1/2 mutations; 4) exemestane and everolimus; and (5) chemotherapy. These strategies are all supported by evidence from clinical trials and retrospective studies. We also describe potential future treatment strategies post CDK4/6 inhibitors, such as the trophoblast cell surface antigen 2 (Trop-2) directed antibody–drug conjugate, cyclin-dependent kinase 7 (CDK7) inhibitors, and B-cell lymphoma-2 (BCL-2) inhibitors.

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“…Activation of the PI3K-AKT-mTOR pathway or cell-cycle promoter CDK4/6 has been shown to be important as the mechanism of how breast cancer acquires resistance to endocrine therapy. Dual inhibition of estrogen with mTOR (everolimus) or CDK4/6 (palbociclib, abemaciclib) is now an option for recurrent/metastatic disease [ 80 , 81 , 82 ].…”

Section: Agents Inhibiting the Effect Of Sex Steroid Hormonesmentioning

confidence: 99%

Carcinogenesis of Triple-Negative Breast Cancer and Sex Steroid Hormones

Honma

Matsuda

Mikami

2021

Cancers

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Triple-negative breast cancer (TNBC) lacks an effective treatment target and is usually associated with a poor clinical outcome; however, hormone unresponsiveness, which is the most important biological characteristic of TNBC, only means the lack of nuclear estrogenic signaling through the classical estrogen receptor (ER), ER-α. Several sex steroid receptors other than ER-α: androgen receptor (AR), second ER, ER-β, and non-nuclear receptors represented by G-protein-coupled estrogen receptor (GPER), are frequently expressed in TNBC and their biological and clinical importance has been suggested by a large number of studies. Despite the structural similarity between each sex steroid hormone (androgens and estrogens) or each receptor (AR and ER-β), and similarity in the signaling mechanisms of these hormones, most studies or reviews focused on one of these receptors, and rarely reviewed them in a comprehensive way. Considering the coexistence of these hormones and their receptors in TNBC in a clinical setting, a comprehensive viewpoint would be important to correctly understand the association between the carcinogenic mechanism or pathobiology of TNBC and sex steroid hormones. In this review, the carcinogenic or pathobiological role of sex steroid hormones in TNBC is considered, focusing on the common and divergent features of the action of these hormones.

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CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives

Cited by 43 publications

References 66 publications

Ecological interactions in breast cancer: Cell facilitation promotes growth and survival under drug pressure

Ecological interactions in breast cancer: Cell facilitation promotes growth and survival under drug pressure

Advances in Therapy for Hormone Receptor (HR)-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced Breast Cancer Patients Who Have Experienced Progression After Treatment with CDK4/6 Inhibitors

Carcinogenesis of Triple-Negative Breast Cancer and Sex Steroid Hormones

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