A proteomic and phosphoproteomic landscape of KRAS mutant cancers identifies combination therapies

Liu, Zhiwei; Liu, Yingluo; Qian, Lili; Jiang, Shangwen; Gai, Xiameng; Ye, Shu; Chen, Yuehong; Wang, Xiaomin; Zhai, Linhui; Xu, Jun; Pu, Congying; Li, Jing; He, Fuchu; Huang, Min; Tan, Minjia

doi:10.1016/j.molcel.2021.07.021

Cited by 38 publications

(24 citation statements)

References 78 publications

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“…Finally, a study of Liu et al (2021 ) showed that DOT1L inhibition, combined with SHP2 blockade, represents an effective means for the treatment of a subset of KRAS-mutant cancers from different tissues. This was demonstrated by the application of the integrative analysis of phosphoproteome and drug sensitivity generated for a group of KRAS-mutant cancer cell lines with distinct biological, clinical, and therapeutic characteristics, representative of tumors with the poorest prognosis.…”

Section: Mechanisms Of Dot1 Action In Solid Tumorsmentioning

confidence: 99%

“…In detail, combination of the two drugs resulted in synergetic inhibition of patient-derived xenograft growth, characterized by an acceptable toxicity level. Further analysis revealed that the observed beneficial effect was associated with DOT1L blockade-induced upregulation of PREX1, which in turn activated MAPK signaling and enhanced vulnerability of tumor cells to SHP2 inhibition ( Liu et al, 2021 ).…”

Section: Mechanisms Of Dot1 Action In Solid Tumorsmentioning

confidence: 99%

“…Finally, DOT1L inhibitors showed effects also in reducing retinoblastoma cells aggressiveness, where they enhanced sensitivity to chemotherapy and affected cell proliferation ( Mao et al, 2021 ). Moreover, combination therapy with DOT1L and SHP2 inhibitors was demonstrated to be effective in treating a specific subset of KRAS-mutant cancers characterized by a very poor prognosis ( Liu et al, 2021 ).…”

Section: Dot1 Pharmacological Inhibitorsmentioning

confidence: 99%

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Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

et al. 2022

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The histone lysine methyltransferase DOT1L (DOT1-like histone lysine methyltransferase) is responsible for the epigenetic regulation of gene expression through specific methylation of lysine79 residue of histone H3 (H3K79) in actively transcribed genes. Its normal activity is crucial for embryonic development and adult tissues functions, whereas its aberrant functioning is known to contribute to leukemogenesis. DOT1L is the only lysine methyltransferase that does not contain a SET domain, which is a feature that allowed the development of selective DOT1L inhibitors that are currently investigated in Phase I clinical trials for cancer treatment. Recently, abnormal expression of this enzyme has been associated with poor survival and increased aggressiveness of several solid tumors. In this review evidences of aberrant DOT1L expression and activity in breast, ovarian, prostate, colon, and other solid tumors, and its relationships with biological and clinical behavior of the disease and response to therapies, are summarized. Current knowledge of the structural basis of DOT1L ability to regulate cell proliferation, invasion, plasticity and stemness, cell cycle progression, cell-to-cell signaling, epithelial-to-mesenchymal transition, and chemoresistance, through cooperation with several molecular partners including noncoding RNAs, is also reviewed. Finally, available options for the treatment of therapeutically challenging solid tumors by targeting DOT1L are discussed.

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Section: Mechanisms Of Dot1 Action In Solid Tumorsmentioning

confidence: 99%

Section: Mechanisms Of Dot1 Action In Solid Tumorsmentioning

confidence: 99%

Section: Dot1 Pharmacological Inhibitorsmentioning

confidence: 99%

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Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

et al. 2022

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“…However, there is no published information about the potential role of phosphatases regulating DNMT1. Further, although the potential for methyltransferase DOT1L as a therapy target in KRAS mutant cancers was recently demonstrated (Liu, Liu et al, 2021), currently there is neither information whether RAS regulates DOT1L phosphorylation, nor any indications for the role of phosphatases on DOT1L phosphoregulation.…”

Section: Introductionmentioning

confidence: 99%

RAS and PP2A activities converge on epigenetic gene regulation

Aakula

Sharma

Tabaro

et al. 2022

Preprint

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RAS-mediated human cell transformation requires inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A). Both RAS and PP2A mediate their effects by phosphoregulation, but phosphoprotein targets and cellular processes in which RAS and PP2A activities converge in human cancers have not been systematically analyzed. Here, based on mass spectrometry phosphoproteome data we discover that phosphosites co-regulated by RAS and PP2A are enriched on proteins involved in epigenetic gene regulation. As examples, RAS and PP2A co-regulate the same phosphorylation sites on HDAC1/2, KDM1A, MTA1/2, RNF168 and TP53BP1. Mechanistically, we validate co-regulation of NuRD chromatin repressor complex by RAS and PP2A. Consistent with their known synergistic effects in cancer, RAS activation and PP2A inhibition resulted in epigenetic reporter de-repression and activation of oncogenic transcription. Notably, transcriptional de-repression by PP2A inhibition was associated with increased euchromatin and decrease in global DNA methylation. Further, targeting of RAS- and PP2A-regulated epigenetic proteins decreased viability of KRAS-mutant human lung cancer cells. Collectively the results indicate that epigenetic protein complexes involved in oncogenic gene expression constitute a significant point of convergence for RAS hyperactivity and PP2A inhibition in cancer. Further, the results provide a rich source for future understanding of phosphorylation as a previously unappreciated layer of regulation of epigenetic gene regulation in cancer, and in other RAS/PP2A-regulated cellular processes.

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“…Another study that combined proteomics with genetic interactions mapping identified novel KRAS interactors of which at least two, RAP1GDS1 and RHOA were selectively required for KRAS‐mutant LUAD [ 119 ]. Other approaches have revealed new drug combinations that were specifically vulnerable to KRAS ‐mutant tumors such as inhibition of DOTL1 and SHP2 [ 120 ] or WEE1 and ERK [ 121 ]. Taken together, these studies highlight the fact that proteomic or proteogenomic analyses can reveal novel vulnerabilities which may prove particularly useful in those tumors that do not respond to any of the strategies described above or in cases of resistance to targeted therapies.…”

Section: Identification Of Novel Vulnerabilities Via Proteogenomic St...mentioning

confidence: 99%

Targeting KRAS mutant lung cancer: light at the end of the tunnel

Drosten

Barbacid

2022

Molecular Oncology

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For decades, KRAS mutant lung adenocarcinomas (LUAD) have been refractory to therapeutic strategies based on personalized medicine owing to the complexity of designing inhibitors to selectively target KRAS and downstream targets with acceptable toxicities. The recent development of selective KRAS G12C inhibitors represents a landmark after 40 years of intense research efforts since the identification of KRAS as a human oncogene. Here, we discuss the mechanisms responsible for the rapid development of resistance to these inhibitors, as well as potential strategies to overcome this limitation. Other therapeutic strategies aimed at inhibiting KRAS oncogenic signaling by targeting either upstream activators or downstream effectors are also reviewed. Finally, we discuss the effect of targeting the mitogen-activated protein kinase (MAPK) pathway, both based on the failure of MEK and ERK inhibitors in clinical trials, as well as on the recent identification of RAF1 as a potential target due to its MAPK-independent activity. These new developments, taken together, are likely to open new avenues to effectively treat KRAS mutant LUAD.

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A proteomic and phosphoproteomic landscape of KRAS mutant cancers identifies combination therapies

Cited by 38 publications

References 78 publications

Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

RAS and PP2A activities converge on epigenetic gene regulation

Targeting KRAS mutant lung cancer: light at the end of the tunnel

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