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Publisher Correction: Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer.

ABSTRACT:

SUBMITTER: Alves CL

PROVIDER: S-EPMC8446011 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Publisher Correction: Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer.

Alves Carla L CL Ehmsen Sidse S Terp Mikkel G MG Portman Neil N Tuttolomondo Martina M Gammelgaard Odd L OL Hundebøl Monique F MF Kaminska Kamila K Johansen Lene E LE Bak Martin M Honeth Gabriella G Bosch Ana A Lim Elgene E Ditzel Henrik J HJ

Nature communications 20210916 1

PMID: 34531405

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Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer.

Project description:CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer. However, most patients will eventually experience disease progression on this combination, underscoring the need for effective subsequent treatments or better initial therapies. Here, we show that triple inhibition with fulvestrant, CDK4/6i and AKT inhibitor (AKTi) durably impairs growth of breast cancer cells, prevents progression and reduces metastasis of tumor xenografts resistant to CDK4/6i-fulvestrant combination or fulvestrant alone. Importantly, switching from combined fulvestrant and CDK4/6i upon resistance to dual combination with AKTi and fulvestrant does not prevent tumor progression. Furthermore, triple combination with AKTi significantly inhibits growth of patient-derived xenografts resistant to combined CDK4/6i and fulvestrant. Finally, high phospho-AKT levels in metastasis of breast cancer patients treated with a combination of CDK4/6i and endocrine therapy correlates with shorter progression-free survival. Our findings support the clinical development of ER, CDK4/6 and AKT co-targeting strategies following progression on CDK4/6i and endocrine therapy combination, and in tumors exhibiting high phospho-AKT levels, which are associated with worse clinical outcome.

| S-EPMC8387387 | biostudies-literature

AKT/mTOR signaling modulates resistance to endocrine therapy and CDK4/6 inhibition in metastatic breast cancers.

Project description:Endocrine therapy (ET) in combination with CDK4/6 inhibition is routinely used as first-line treatment for HR+/HER2- metastatic breast cancer (MBC) patients. However, 30-40% of patients quickly develop disease progression. In this open-label multicenter clinical trial, we utilized a hypothesis-driven protein/phosphoprotein-based approach to identify predictive markers of response to ET plus CDK4/6 inhibition in pre-treatment tissue biopsies. Pathway-centered signaling profiles were generated from microdissected tumor epithelia and surrounding stroma/immune cells using the reverse phase protein microarray. Phosphorylation levels of the CDK4/6 downstream substrates Rb (S780) and FoxM1 (T600) were higher in patients with progressive disease (PD) compared to responders (p = 0.02). Systemic PI3K/AKT/mTOR activation in tumor epithelia and stroma/immune cells was detected in patients with PD. This activation was not explained by underpinning genomic alterations alone. As the number of FDA-approved targeted compounds increases, functional protein-based signaling analyses may become a critical component of response prediction and treatment selection for MBC patients.

| S-EPMC9935518 | biostudies-literature

Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer.

Project description:Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains first-line therapy for the management of estrogen receptor (ESR1)-positive breast cancer. However, ESR1 mutations or other ligand-independent ESR1 activation mechanisms limit the duration of response. The clinical efficacy of fulvestrant, a selective estrogen receptor downregulator (SERD) that competitively inhibits agonist binding to ESR1 and triggers receptor downregulation, has confirmed that ESR1 frequently remains engaged in endocrine therapy-resistant cancers. We evaluated the activity of a new class of selective estrogen receptor modulators (SERM)/SERD hybrids (SSH) that downregulate ESR1 in relevant models of endocrine-resistant breast cancer. Building on the observation that concurrent inhibition of ESR1 and the cyclin-dependent kinases 4 and 6 (CDK4/6) significantly increased progression-free survival in advanced patients, we explored the activity of different SERD- or SSH-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant ESR1(+) breast cancer.SERDs, SSHs, and the CDK4/6 inhibitor palbociclib were evaluated as single agents or in combination in established cellular and animal models of endocrine therapy-resistant ESR1(+) breast cancer.The combination of palbociclib with a SERD or an SSH was shown to effectively inhibit the growth of MCF7 cell or ESR1-mutant patient-derived tumor xenografts. In tamoxifen-resistant MCF7 xenografts, the palbociclib/SERD or SSH combination resulted in an increased duration of response as compared with either drug alone.A SERD- or SSH-palbociclib combination has therapeutic potential in breast tumors resistant to endocrine therapies or those expressing ESR1 mutations. See related commentary by DeMichele and Chodosh, p. 4999.

| S-EPMC4644714 | biostudies-literature

Publisher Correction to: Palaeoecological differences underlie rare co-occurrence of Miocene European primates.

Project description: Not available

| S-EPMC8323285 | biostudies-literature

Targeting WEE1 Inhibits Growth of Breast Cancer Cells That Are Resistant to Endocrine Therapy and CDK4/6 Inhibitors.

Project description:Despite the success of antiestrogens in extending overall survival of patients with estrogen receptor positive (ER+) breast tumors, resistance to these therapies is prevalent. ER+ tumors that progress on antiestrogens are treated with antiestrogens and CDK4/6 inhibitors. However, 20% of these tumors never respond to CDK4/6 inhibitors due to intrinsic resistance. Here, we used endocrine sensitive ER+ MCF7 and T47D breast cancer cells to generate long-term estrogen deprived (LTED) endocrine resistant cells that are intrinsically resistant to CDK4/6 inhibitors. Since treatment with antiestrogens arrests cells in the G1 phase of the cell cycle, we hypothesized that a defective G1 checkpoint allows resistant cells to escape this arrest but increases their dependency on G2 checkpoint for DNA repair and growth, and hence, targeting the G2 checkpoint will induce cell death. Indeed, inhibition of WEE1, a crucial G2 checkpoint regulator, with AZD1775 (Adavosertib), significantly decreased cell proliferation and increased G2/M arrest, apoptosis and gamma-H2AX levels (a marker for DNA double stranded breaks) in resistant cells compared with sensitive cells. Thus, targeting WEE1 is a promising anti-cancer therapeutic strategy in standard therapy resistant ER+ breast cancer.

| S-EPMC8281892 | biostudies-literature

Publisher Correction: N6-methyladenosine-modified ALDH9A1 modulates lipid accumulation and tumor progression in clear cell renal cell carcinoma through the NPM1/IQGAP2/AKT signaling pathway.

Project description: Not available

| S-EPMC11362545 | biostudies-literature

Publisher Correction: Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma.

Project description:In the version of this article originally published, there was an error in the URL linked to by an accession code in the data availability section of the methods. The erroneous URL was: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE100351 . The correct URL is: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE115821 . The error has been corrected in the HTML and PDF versions of this article.

| S-EPMC9639231 | biostudies-literature

Correction: CDKL3 promotes osteosarcoma progression by activating Akt/PKB.

Project description: Not available

| S-EPMC9603691 | biostudies-literature

Comparative Overall Survival of CDK4/6 Inhibitors Plus Endocrine Therapy vs. Endocrine Therapy Alone for Hormone receptor-positive, HER2-negative metastatic breast cancer.

Project description:Background: The combination of CDK4/6 inhibitors and endocrine therapy has greatly improved progression-free survival (PFS) in patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer in many randomized controlled trials (RCTs). However, the key issue was the extent to which the benefit in PFS could translate into a prolongation of OS. Methods: We performed a systematical literature search of PubMed, Web of Science, Cochrane Central Register of Clinical Trials and Embase, as well as meeting online archives up to February 2020. The primary outcome was OS, and we performed indirect treatment comparisons depend on a meta-analysis. Results: Six RCTs were eligible including 3421 breast cancer patients. Compared to the endocrine therapy alone group, adding CDK4/6 inhibitors to endocrine therapy had significantly improved OS (HR=0.76, 95% CI=0.68-0.85, P<0.001). Moreover, the OS advantage was consistent in patients with different combined endocrine therapy, endocrine sensitivity status, sites of distant metastasis, menopausal status and age. Nevertheless, more adverse events were observed in patients treated with CDK4/6 inhibitors. The most common grade 3-4 adverse events were neutropenia (risk ratio [RR]=37.15, 95% CI=15.33-90.04), leucopenia (RR=25.58, 95% CI=13.23-49.46) and anaemia (RR=2.24, 95% CI=1.38-3.85). Conclusions: Our meta-analysis suggested that compared with endocrine therapy alone, the addition of CDK4/6 inhibitors significantly improved OS in patients with hormone receptor-positive, HER2-negative metastatic breast cancer. However, the addition of CDK4/6 inhibitors also increased the incidences of grade 3-4 adverse events.

| S-EPMC7646186 | biostudies-literature

Publisher Correction: The role of Patronin in Drosophila mitosis.

Project description:During production of the original article [1], there was a technical error that resulted in author corrections not being rendered in the PDF version of the article.

| S-EPMC6615211 | biostudies-literature

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