The Molecular Context of Vulnerability for CDK9 Suppression in Triple Wild-Type Melanoma

Guhan, Samantha; Shaughnessy, Michael F.; Rajadurai, Anpuchchelvi; Taylor, Michael; Kumar, Raj; Ji, Zhenyu; Rashid, Sarem; Flaherty, Keith T.

doi:10.1016/j.jid.2020.12.035

Cited by 9 publications

(12 citation statements)

References 33 publications

(34 reference statements)

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“…c. Two-dimensional and three-dimensional cell cultures showed significantly more cell death in BNFwt cell lines than in BNFmut cell lines on CDK9 inhibition: In Figure 2 of Guhan et al (2021), BNFwt cell lines were shown to have a significantly higher number of dead cells with TS-032 or NVP-2 treatment than BNFmut and primary cells. These results show the sensitivity of BNFwt to CDK9 inhibition but do not explain the underlying mechanism of this sensitivity.…”

Section: Discussion Of Incorrect Answersmentioning

confidence: 99%

“…b. Pol-II-carboxy-terminal domain is consistently abrogated by NVP-2 treatment: Figure 3a of Guhan et al (2021) shows the level of CDK9 and its phosphorylated serine-2 (pSer2) carboxy-terminal domain (CTD) in BNFmut and BNFwt cell lines after treatment with either TS-032 or NVP-2, both of which are CDK9 inhibitors. Both CDK9 and Pol-II-CTD (pSer2), a known target of CDK9, are abrogated to different extents by NVP-2 and TS-032 across all samples.…”

Section: Discussion Of Incorrect Answersmentioning

confidence: 99%

“…2. According to Guhan et al (2021), the sensitivity of BRAF/NRAS/NF1ewild-type (BNFwt) melanomas to CDK9 inhibition could be attributed to their dependencies on a transcriptional network. Which of the following findings best supports this statement?…”

Section: According Tomentioning

confidence: 99%

“…To determine the molecular pathways that distinguish BNFwt from BRAF/NRAS/NF1-mutant (BNFmut) tumor cell lines, Guhan et al (2021) identified 2,029 genes that were differentially expressed between BNFwt and BNFmut after NVP-2 treatment. Genes that were more significantly depleted in BNFwt than in BNFmut were subjected to transcription factor (TF) target enrichment and network analyses with chromatin immunoprecipitationeX enrichment analysis 3 (ChEA3), which reveal a significant association with the E2F network.…”

Section: According Tomentioning

confidence: 99%

“…Furthermore, E2F1 and E2F2 are expressed at a significantly higher level in BNFwt than in BNFmut melanomas without CDK9 inhibition. Following these findings, Guhan et al (2021) drew a direct link between transcriptional network and CDK9 inhibition by showing a significant correlation between CDK9 expression and E2F1/2 expression levels. Taken together, these results suggest that BNFwt melanomas can be distinguished from BNFmut melanomas by differential expression of the E2F network, and their dependencies on this transcription network may contribute to their vulnerability to CKD9 inhibition.…”

Section: According Tomentioning

confidence: 99%

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Section: Discussion Of Incorrect Answersmentioning

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Section: According Tomentioning

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Section: According Tomentioning

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RAC1 P29S is the third most prevalent hotspot mutation in sun-exposed melanoma. RAC1 alterations in cancer are correlated with poor prognosis, resistance to standard chemotherapy, and insensitivity to targeted inhibitors. Although RAC1 P29S mutations in melanoma and RAC1 alterations in several other cancers are increasingly evident, the RAC1-driven biological mechanisms contributing to tumorigenesis remain unclear. Lack of rigorous signaling analysis has prevented identi cation of alternative therapeutic targets for RAC1 P29S -harboring melanomas. To investigate the RAC1 P29S -driven effect on downstream molecular signaling pathways, we generated an inducible RAC1 P29S expression melanocytic cell line and performed RNA-sequencing (RNA-seq) coupled with multiplexed kinase inhibitor beads and mass spectrometry (MIBs/MS) to establish enriched pathways from the genomic to proteomic level. Our proteogenomic analysis identi ed CDK9 as a potential new and speci c target in RAC1 P29S -mutant melanoma cells. In vitro, CDK9 inhibition impeded the proliferation of in RAC1 P29S -mutant melanoma cells and increased surface expression of PD-L1 and MHC Class I proteins. In vivo, combining CDK9 inhibition with anti-PD-1 immune checkpoint blockade signi cantly inhibited tumor growth only in melanomas that expressed the RAC1 P29S mutation. Collectively, these results establish CDK9 as a novel target in RAC1-driven melanoma that can further sensitize the tumor to anti-PD-1 immunotherapy.

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The Molecular Context of Vulnerability for CDK9 Suppression in Triple Wild-Type Melanoma

Cited by 9 publications

References 33 publications

SnapshotDx Quiz: November 2021

SnapshotDx Quiz: November 2021

Targeting cyclin-dependent kinases: From pocket specificity to drug selectivity

Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints

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