CDK4/6 Inhibition Reprograms Mitochondrial Metabolism in BRAFV600 Melanoma via a p53 Dependent Pathway

Santiappillai, Nancy; AbuHammad, Shatha; Slater, Alison; Kirby, Laura; McArthur, Grant A.; Sheppard, Karen E.; Smith, Lorey

doi:10.3390/cancers13030524

Cited by 16 publications

(9 citation statements)

References 44 publications

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“…Integrating single-cell and bulk RNA-seq data, we observed the perturbation of OxPhos in all cell lines. This is in line with previous works demonstrating metabolic adaptation after MAPK inhibition or CDK4/6i in BRAF mutant and uveal melanoma [68,69]. Moreover, OxPhos metabolism has been previously reported as a generic drug resistance mechanism and as a key decision point between cell death and survival [70,71].…”

Section: Discussionsupporting

confidence: 92%

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

Gureghian

Herbst

Kozar

et al. 2023

Preprint

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Therapy Induced Senescence (TIS) leads to sustained growth arrest of cancer cells. Conversely, the Senescence Associated Secretory Phenotype (SASP) has been shown to promote tumorigenesis and metastasis. The associated cytostasis, which was first conceived as permanent, has since been shown to be reversible. Cells escaping senescence further enhance the aggressiveness of cancers. Despite all this, the mechanisms by which cancer cells escape senescence are poorly understood and the development of specific and efficient 'senolytics', specifically targeting senescent cancer cells, is in its infancy. Together with targeted therapeutics, senolytics constitute a promising avenue for improved cancer treatments. Understanding how cancer cells evade senescence is needed to optimize the clinical benefits of this promising approach. Here we characterized the response of three different NRAS mutant melanoma cell lines to a combination of CDK4/6 and MEK inhibitors over 33 days. Transcriptomic data show that all cell lines trigger a senescence program coupled with strong induction of interferons. Kinome profiling revealed the activation of Receptor Tyrosine Kinases (RTKs) and enriched downstream signaling of neurotrophin, ErbB and insulin pathways. Characterization of the miRNA interactome associates miR-211-5p with resistant phenotypes. Finally, integration of bulk and single-cell RNA-seq data identified biological processes perturbed during senescence establishment and escape, and predicts new genes involved in this shift. Overall, our data associate insulin signaling with persistence of a senescent phenotype and suggest a new role for interferon gamma in senescence escape through the induction of EMT and the activation of ERK5 signaling.

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Section: Discussionsupporting

confidence: 92%

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

Gureghian

Herbst

Kozar

et al. 2023

Preprint

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“…This study generated a triple knockout of all three PCL proteins (PHF1, MTF2 and PHF19), resulting in complete ablation of all PRC2.1 activity and did not probe the contribution of each accessory protein individually. Furthermore, MTF2 transcript levels are down regulated upon differentiation, whereas PHF1 and PHF19 levels increase 99 . These data suggest that the subunit composition of PRC2.1 changes during this process.…”

Section: Discussionmentioning

confidence: 99%

The PRC2.1 Subcomplex Opposes G1 Progression through Regulation of CCND1 and CCND2

Longhurst,

Wang,

Suresh

et al. 2024

Preprint

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Progression through the G1 phase of the cell cycle is the most highly regulated step in cellular division. We employed a chemogenomics approach to discover novel cellular networks that regulate cell cycle progression. This approach uncovered functional clusters of genes that altered sensitivity of cells to inhibitors of the G1/S transition. Mutation of components of the Polycomb Repressor Complex 2 rescued growth inhibition caused by the CDK4/6 inhibitor palbociclib, but not to inhibitors of S phase or mitosis. In addition to its core catalytic subunits, mutation of the PRC2.1 accessory protein MTF2, but not the PRC2.2 protein JARID2, rendered cells resistant to palbociclib treatment. We found that MTF2-containing PRC2.1, but not JARID2-containing PRC2.2, was critical for promoting H3K27me3 deposition at CpG islands genome-wide and in promoters. This included the CpG islands in the promoter of the CDK4/6 cyclins CCND1 and CCND2, and loss of MTF2 lead to upregulation of both CCND1 and CCND2. Our results demonstrate a role for PRC2.1, but not PRC2.2, in promoting G1 progression.

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“…The XF Cell Mito Stress Test was performed as previously described [ 25 ]. Cells were seeded on Seahorse XF 96 well cell culture plates (5000–14,000 cells per well) 48 h prior to analysis (quadruplicate wells per condition).…”

Section: Methodsmentioning

confidence: 99%

Phenotypic Consequences of SLC25A40-ABCB1 Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer

Pishas

Cowley

Pandey

et al. 2021

Cancers

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Despite high response rates to initial chemotherapy, the majority of women diagnosed with High-Grade Serous Ovarian Cancer (HGSOC) ultimately develop drug resistance within 1–2 years of treatment. We previously identified the most common mechanism of acquired resistance in HGSOC to date, transcriptional fusions involving the ATP-binding cassette (ABC) transporter ABCB1, which has well established roles in multidrug resistance. However, the underlying biology of fusion-positive cells, as well as how clonal interactions between fusion-negative and positive populations influences proliferative fitness and therapeutic response remains unknown. Using a panel of fusion-negative and positive HGSOC single-cell clones, we demonstrate that in addition to mediating drug resistance, ABCB1 fusion-positive cells display impaired proliferative capacity, elevated oxidative metabolism, altered actin cellular morphology and an extracellular matrix/inflammatory enriched transcriptional profile. The co-culture of fusion-negative and positive populations had no effect on cellular proliferation but markedly altered drug sensitivity to doxorubicin, paclitaxel and cisplatin. Finally, high-throughput screening of 2907 FDA-approved compounds revealed 36 agents that induce equal cytotoxicity in both pure and mixed ABCB1 fusion populations. Collectively, our findings have unraveled the underlying biology of ABCB1 fusion-positive cells beyond drug resistance and identified novel therapeutic agents that may significantly improve the prognosis of relapsed HGSOC patients.

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CDK4/6 Inhibition Reprograms Mitochondrial Metabolism in BRAFV600 Melanoma via a p53 Dependent Pathway

Cited by 16 publications

References 44 publications

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

The PRC2.1 Subcomplex Opposes G1 Progression through Regulation of CCND1 and CCND2

Phenotypic Consequences of SLC25A40-ABCB1 Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer

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