Massive chromatin remodeling underlies key biological effects of CDK4/6 inhibitors
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ABSTRACT:
PROVIDER: PRJNA547774 | ENA |
REPOSITORIES: ENA
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Project description:CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.
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Project description:The CDK4/6 kinase is dysregulated in melanoma highlighting a potential therapeutic benefit. Indeed, such CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern and the molecular mechanisms of such resistance remain undefined. Here, we demonstrate that reactivation of mTORC1 signaling through increased expression of the amino acid transporter, SLC36A1, drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms; 1) Rb loss which drives SLC36A1 via reduced suppression of E2f; 2) FXR1 overexpression which promotes SLC36A1 translation and subsequently mTORC1. Finally, we demonstrate that a combination of a CDK4/6 inhibitor with an mTORC1 inhibitor has increased therapeutic efficacy in vivo providing an important avenue for improved therapeutic intervention in aggressive melanoma.
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Project description:This data set belongs to the publication 'Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders' from Xuewei Wu et al (PI: Poulikos I. Poulikakos) and contains the mass spectrometry files for affinity purification of endogenous CDK6 from tumor cell lines either sensitive or resistant to CDK4/6 inhibitors. The data showed a higher degree of interaction of CDK6 with components of the HSP90/CDC37 chaperoning complex in CDK4/6i-sensitive compared to CDK4/6i-resistant cells.
2020-12-09 | MSV000086571 | MassIVE
Project description:CDK4/6 inhibitors arrest the cell cycle in G1-phase. They are licenced to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a temporary cell cycle arrest in G1 causes long-lasting effects on tumour growth. Here we demonstrate that a prolonged G1-arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. This causes a failure in DNA replication after release from that arrest, resulting in a p53-dependent withdrawal from the cell cycle. If p53 is absent, then cells bypass the G2-checkpoint and undergo a catastrophic mitosis resulting in excessive DNA damage. These data therefore link CDK4/6 inhibition to genotoxic stress; a phenotype that is shared by most other broad-spectrum anti-cancer drugs. This provides a rationale to predict responsive tumour types and effective combination therapies, as demonstrated by the fact that chemotherapeutics that cause replication stress also induce sensitivity to CDK4/6 inhibition.
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2019-02-04 | GSE120298 | GEO
Project description:Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16INK4a-deficient profile associated with positive responses to CDK4/6 inhibitors. Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT. Moreover, our study suggests a novel paradigm whereby critically low oncogene levels, caused by loss of a driver tumor suppressor, may also be exploited therapeutically.
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Project description:This is the raw proteomics data of H1299 cell before and after resistance to cdk4/6 inhibitors
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