Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor

Freeman‐Cook, Kevin D.; Hoffman, Robert; Miller, Nichol L.G.; Almaden, Jonathan; Chionis, John; Zhang, Qin; Eisele, Koleen; Liu, Chaoting; Zhang, Cathy; Huser, Nanni; Nguyen, Lisa; Costa-Jones, Cinthia; Niessen, Sherry; Carelli, Jordan D; Lapek, John D.; Weinrich, Scott L.; Wei, Ping; McMillan, Elizabeth A.; Wilson, Elizabeth A.; Wang, Tim S.; McTigue, Michele; Ferre, Rose Ann; He, You-Ai; Ninkovic, Sacha; Behenna, Douglas C.; Tran, Khanh; Sutton, Scott C.; Nagata, Asako; Ornelas, Martha A.; Kephart, Susan E.; Zehnder, Luke R.; Murray, Brion W.; Xu, Meirong; Solowiej, James; Visswanathan, Ravi; Boras, Britton; Looper, David; Lee, Nathan; Bienkowska, Jadwiga; Zhu, Zhou; Kan, Zhengyan; Ding, Ying; Mu, Xinmeng Jasmine; Oderup, Cecilia; Salek-Ardakani, Shahram; White, Michael A.; VanArsdale, Todd; Dann, Stephen G.

doi:10.1016/j.ccell.2021.08.009

Cited by 106 publications

(63 citation statements)

References 88 publications

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“…In MAINTAIN, a phase II randomized trial on CDK4/6i-resistant patients evaluating the switch of anti-estrogen therapy and either ribociclib or placebo, most patients also switched to a different CDK4/6i (11% of the full cohort had prior ribociclib), and they found a statistically significant improvement in the ribociclib arm compared to the placebo arm (median PFS of 5.33 vs 2.76 months, respectively) (Kalinsky et al 2022). Although in vitro and in vivo work suggest that ribociclib and palbociclib have similar pharmacological profiles and only abemaciclib differs from them (because of its CDK2 and CDK9 activity) (Freeman-Cook et al 2021;Hafner et al 2019), the results of MAINTAIN, and the large difference in CBR between our trial and TRINITI-1 (18.8% vs 65.2% or 59.4%) points to the possibility that switching between distinct CDK4/6 inhibitors might be a strong contributor to this difference.…”

Section: Differences In Clinical Benefit Rate Between Triple Therapy ...mentioning

confidence: 99%

Genomic and Transcriptomic Determinants of Resistance to CDK4/6 Inhibitors and Response to Combined Exemestane plus Everolimus and Palbociclib in Patients with Metastatic Hormone Receptor Positive Breast Cancer

Zañudo

Barroso‐Sousa

Jain

et al. 2022

Preprint

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Even though multiple resistance mechanisms and pathways for cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have been discovered, the complete landscape of resistance is still being elucidated. Moreover, the optimal subsequent therapy to overcome resistance remains uncertain. To address this, we carried out a phase I/II clinical trial of exemestane plus everolimus and palbociclib, triplet therapy for CDK4/6i-resistant hormone receptor-positive (HR+), HER2- metastatic breast cancer, one of the first trials evaluating CDK4/6i after CDK4/6i progression. With an observed clinical benefit rate of 18.8% (n = 6/32), the trial did not meet its primary efficacy endpoint. However, we leveraged the multi-omics tumor data from these patients to study the landscape of CDK4/6i resistance and to identify correlates of response to triplet therapy. We generated whole exome sequencing from 24 tumor and 17 ctDNA samples and transcriptome sequencing from 27 tumor samples obtained from 26 patients in the trial. Genomic and evolutionary analysis recapitulated the spectrum of known resistance genes (ERBB2, NF1, AKT1, RB1, ESR1) and pathways (RTK/MAPK, PI3K/AKT/mTOR, cell cycle, estrogen receptor), discovered potential new mechanisms of resistance in these pathways (ERBB2 amplification, BRAFV600E, MTORT1977R), and identified a patient with co-existing tumor lineages with distinct activating ERBB2 mutations, potentially the first case of convergent evolution of HER2 activation following CDK4/6i therapy. Joint genomic and transcriptomic analysis revealed that genomic resistance mechanisms were associated with transcriptomic features in their respective pathways, suggesting that transcriptomic features could be used to identify the pathways driving resistance. In particular, the mutually exclusive ESR1 and ERBB2/BRAF mutations, were each linked with high activity in distinct pathway signatures (estrogen receptor pathway vs RTK/MAPK pathway, respectively) and were exclusive to distinct molecular subtypes (Luminal A or Luminal B vs HER2-E, respectively). Overall, incorporating clinical and multi-omics features in CDK4/6i-resistant tumors enabled identification of known or putative drivers of resistance to the prior CDK4/6i and anti-estrogen therapies in nearly every patient (n = 22/23), including several patients in which transcriptomic features were the sole drivers. Genomic and transcriptomic features - particularly PI3K/AKT/mTOR mutations and/or high mTORC1 pathway activity - suggested that clinical benefit to combined estrogen receptor, CDK4/6, and mTOR inhibition was correlated with activation of the mTOR pathway. Our results illustrate how transcriptome sequencing provides complementary and additional information to genome sequencing, and how integrating both may help better identify patients likely to respond to CDK4/6i therapies.

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Section: Differences In Clinical Benefit Rate Between Triple Therapy ...mentioning

confidence: 99%

Genomic and Transcriptomic Determinants of Resistance to CDK4/6 Inhibitors and Response to Combined Exemestane plus Everolimus and Palbociclib in Patients with Metastatic Hormone Receptor Positive Breast Cancer

Zañudo

Barroso‐Sousa

Jain

et al. 2022

Preprint

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“…Recently, cell cycle inhibitors have shown remarkable antitumor properties on several malignancies, indicating their potential in tumor therapy [65][66][67]. e advancement of four distinct phases of the cell cycle, which are regulated by cyclins and CDKs, is required for cell proliferation [68].…”

Section: Discussionmentioning

confidence: 99%

APY0201 Represses Tumor Growth through Inhibiting Autophagy in Gastric Cancer Cells

Jin

Zhang

et al. 2022

Journal of Oncology

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Gastric cancer (GC) is one of the most common cancers globally. There are currently few effective chemotherapeutic drugs available for GC patients. The inhibitors of phosphatidylinositol kinase containing an FYVE finger structure (PIKfyve) have shown significant anticancer effects in several types of cancers, but their effectiveness in GC remains unknown. In this study, we investigate the effect of APY0201, an inhibitor of PIKfyve, on GC tumor growth and its mechanism of action. It was found that APY0201 inhibited GC cell proliferation in in vitro GC cell model, organoid model, and in vivo xenograft tumor model. Through analyzing cell autophagy, we found that APY0201 might block autophagic flux by impairing lysosome degradation function of GC cells, inducing the accumulation of autophagosomes, thus causing the inhibition of GC cell proliferation. We also found that APY0201 induced G1/S phase arrest in GC cells. Importantly, APY0201 was also effective in inducing repression of autophagy and cell cycle arrest in the mouse tumor xenograft. Our results suggest that APY0201 could be a new promising therapeutic option for GC.

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“…Qualitative and/or quantitative alterations in some cell-cycle checkpoints are also responsible for chemo- or radio-resistance in several cancers, including GBM [ 81 ]. Selected checkpoints are druggable, sometimes highly selectively, by specific molecules that can thus interfere with cell replication at different steps [ 50 , 82 ]. In this context, some antipsychotics, i.e., CPZ, THD, TFP and the phenothiazine derivative DS00329, may induce cell-cycle arrest in G1 [ 52 , 83 , 84 , 85 , 86 ].…”

Section: The Role Of Antipsychotics In Hindering the Growth Of Gbm Cells At The Ten Cancer Hallmarksmentioning

confidence: 99%

Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma

Persico¹,

Abbruzzese²,

Matteoni³

et al. 2022

Cells

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Glioblastoma (GBM) is associated with a very dismal prognosis, and current therapeutic options still retain an overall unsatisfactorily efficacy in clinical practice. Therefore, novel therapeutic approaches and effective medications are highly needed. Since the development of new drugs is an extremely long, complex and expensive process, researchers and clinicians are increasingly considering drug repositioning/repurposing as a valid alternative to the standard research process. Drug repurposing is also under active investigation in GBM therapy, since a wide range of noncancer and cancer therapeutics have been proposed or investigated in clinical trials. Among these, a remarkable role is played by the antipsychotic drugs, thanks to some still partially unexplored, interesting features of these agents. Indeed, antipsychotic drugs have been described to interfere at variable incisiveness with most hallmarks of cancer. In this review, we analyze the effects of antipsychotics in oncology and how these drugs can interfere with the hallmarks of cancer in GBM. Overall, according to available evidence, mostly at the preclinical level, it is possible to speculate that repurposing of antipsychotics in GBM therapy might contribute to providing potentially effective and inexpensive therapies for patients with this disease.

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Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor

Cited by 106 publications

References 88 publications

Genomic and Transcriptomic Determinants of Resistance to CDK4/6 Inhibitors and Response to Combined Exemestane plus Everolimus and Palbociclib in Patients with Metastatic Hormone Receptor Positive Breast Cancer

Genomic and Transcriptomic Determinants of Resistance to CDK4/6 Inhibitors and Response to Combined Exemestane plus Everolimus and Palbociclib in Patients with Metastatic Hormone Receptor Positive Breast Cancer

APY0201 Represses Tumor Growth through Inhibiting Autophagy in Gastric Cancer Cells

Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma

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