Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas.

Published on Sep 1, 2020in Molecular Cancer Therapeutics5.615
· DOI :10.1158/1535-7163.MCT-19-0958
Mara Gilardi11
Estimated H-index: 11
(UCSD: University of California, San Diego),
Zhiyong Wang51
Estimated H-index: 51
(UCSD: University of California, San Diego)
+ 11 AuthorsFrancis Burrows29
Estimated H-index: 29
Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). FT catalyzes the post-translational attachment of farnesyl groups to signaling proteins that are required for localization to cell membranes. Although all RAS isoforms are FT substrates, only HRAS is exclusively dependent upon farnesylation, raising the possibility that HRAS mutant tumors might be susceptible to tipifarnib-mediated inhibition of FT. Here, we report the characterization of tipifarnib activity in a wide panel of HRAS mutant and wild type HNSCC xenograft models. Tipifarnib treatment displaced both mutant and wild type HRAS from membranes but only inhibited proliferation, survival and spheroid formation of HRAS mutant cells. In vivo, tipifarnib treatment induced tumor stasis or regression in all six HRAS mutant xenografts tested but displayed no activity in six HRAS wild type PDX models. Mechanistically, drug treatment resulted in reduction of MAPK pathway signaling, inhibition of proliferation and induction of apoptosis and robust abrogation of neovascularization, apparently via effects on both tumor cells and endothelial cells. Bioinformatics and quantitative image analysis further revealed that FT inhibition induces progressive squamous cell differentiation in tipifarnib-treated HNSCC PDX. These preclinical findings support that HRAS represents a druggable oncogene in HNSCC through FT inhibition by tipifarnib, thereby identifying a precision therapeutic option for HNSCCs harboring HRAS mutations.
📖 Papers frequently viewed together
21 Citations
106 Citations
12 Citations
#1Elisabeth M. Storck (Imperial College London)H-Index: 8
#2Julia Morales-Sanfrutos (Imperial College London)H-Index: 20
Last. Edward W. Tate (Imperial College London)H-Index: 39
view all 11 authors...
Post-translational farnesylation or geranylgeranylation at a C-terminal cysteine residue regulates the localization and function of over 100 proteins, including the Ras isoforms, and is a therapeutic target in diseases including cancer and infection. Here, we report global and selective profiling of prenylated proteins in living cells enabled by the development of isoprenoid analogues YnF and YnGG in combination with quantitative chemical proteomics. Eighty prenylated proteins were identified in...
33 CitationsSource
#1Tapesh Santra (UCD: University College Dublin)H-Index: 9
#2Ana Herrero (UCD: University College Dublin)H-Index: 7
Last. Walter Kolch (UCD: University College Dublin)H-Index: 94
view all 14 authors...
Modern omics technologies allow us to obtain global information on different types of biological networks. However, integrating these different types of analyses into a coherent framework for a comprehensive biological interpretation remains challenging. Here, we present a conceptual framework that integrates protein interaction, phosphoproteomics, and transcriptomics data. Applying this method to analyze HRAS signaling from different subcellular compartments shows that spatially defined network...
15 CitationsSource
Although the molecular landscape of squamous cell carcinoma of the head and neck (SCCHN) has been largely deciphered, only one targeted therapy has been approved to date without any molecular selection, namely cetuximab. Cetuximab is a monoclonal antibody targeting EGFR. It has been shown to improve overall survival in the locally advanced setting in combination with radiotherapy and the recurrent and/or metastatic setting in combination with a platinum compound and 5FU. Beside EGFR targeting ag...
10 CitationsSource
#1Siqi Li (Duke University)H-Index: 2
#2Allan Balmain (UCSF: University of California, San Francisco)H-Index: 80
Last. Christopher M. Counter (Duke University)H-Index: 57
view all 3 authors...
The three RAS genes — HRAS, NRAS and KRAS — are collectively mutated in one-third of human cancers, where they act as prototypic oncogenes. Interestingly, there are rather distinct patterns to RAS mutations; the isoform mutated as well as the position and type of substitution vary between different cancers. As RAS genes are among the earliest, if not the first, genes mutated in a variety of cancers, understanding how these mutation patterns arise could inform on not only how cancer begins but al...
88 CitationsSource
#1Alan Loh Ho (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 10
#2Nicole G. Chau (Harvard University)H-Index: 21
Last. A. GualbertoH-Index: 3
view all 17 authors...
14 CitationsSource
#1Ian Y. LukH-Index: 2
Last. John M. MariadasonH-Index: 57
view all 3 authors...
The epithelium-specific ETS (ESE) transcription factors (ELF3, ELF5, EHF and SPDEF) are defined by their highly conserved ETS DNA binding domain and predominant epithelial-specific expression profile. ESE transcription factors maintain normal cell homeostasis and differentiation of a number of epithelial tissues, and their genetic alteration and deregulated expression has been linked to the progression of several epithelial cancers. Herein we review the normal function of the ESE transcription f...
28 CitationsSource
#1Brian R. Untch (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 21
#2Vanessa Dos Anjos (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 1
Last. James A. Fagin (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 97
view all 11 authors...
Of the three RAS oncoproteins, only HRAS is delocalized and inactivated by farnesyltransferase inhibitors (FTI), an approach yet to be exploited clinically. In this study, we treat mice bearing Hras-driven poorly differentiated and anaplastic thyroid cancers (Tpo-Cre/HrasG12V/p53flox/flox) with the FTI tipifarnib. Treatment caused sustained tumor regression and increased survival; however, early and late resistance was observed. Adaptive reactivation of RAS-MAPK signaling was abrogated in vitro ...
21 CitationsSource
#1Claudia Corbo (Brigham and Women's Hospital)H-Index: 23
#2Morteza Mahmoudi (Brigham and Women's Hospital)H-Index: 85
Last. Omid C. Farokhzad (Brigham and Women's Hospital)H-Index: 104
view all 3 authors...
Despite recent progress in nanomedicine, there is still a lack of efficient nanotherapeutics for cancer treatment. When nanoparticles (NPs) are injected, they circulate the bloodstream and interact with biomolecules, creating a biomolecular shell. This shell of biomolecules surrounding the NPs consists mostly of proteins and is referred to as the protein corona (PC). The PC composition depends on various factors, including, but not limited to i) surface properties of NPs (e.g. surface chemistry ...
6 CitationsSource
#1Katherine A. Hoadley (UNC: University of North Carolina at Chapel Hill)H-Index: 8
#1Katherine A. Hoadley (UNC: University of North Carolina at Chapel Hill)H-Index: 81
Last. Christopher C. Benz (Buck Institute for Research on Aging)H-Index: 84
view all 23 authors...
We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. ...
680 CitationsSource
#1Matthew R. JanesH-Index: 5
#2Jingchuan ZhangH-Index: 3
Last. Yi LiuH-Index: 26
view all 34 authors...
Summary KRAS G12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRAS G12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro ; however, it is uncertain whether this approach would transla...
330 CitationsSource
Cited By8
#1Alexander T. Pearson (U of C: University of Chicago)H-Index: 18
#2Everett E. Vokes (U of C: University of Chicago)H-Index: 120
Since coronavirus disease 2019 (COVID-19) is a serious new worldwide public health crisis with significant morbidity and mortality, effective therapeutic treatments are urgently needed. Drug repurposing is an efficient and cost-effective strategy with minimum risk for identifying novel potential treatment options by repositioning therapies that were previously approved for other clinical outcomes. Here, we used an integrated network-based pharmacologic and transcriptomic approach to screen drug ...
#1Zuzana Saidak (University of Picardie Jules Verne)H-Index: 13
#2Claire Lailler (University of Picardie Jules Verne)H-Index: 2
Last. Antoine Galmiche (University of Picardie Jules Verne)H-Index: 24
view all 6 authors...
BACKGROUND Oral squamous cell carcinoma (OSCC) is the most frequent type of tumor arising from the oral cavity. Surgery is the cornerstone of the treatment of these cancers. Tumor biology has long been overlooked as an important contributor to the outcome of surgical procedures, but recent studies are challenging this concept. Molecular analyses of tumor DNA or RNA provide a rich source of information about the biology of OSCC. METHODS We searched for relevant articles using PubMed. We examined ...
1 CitationsSource
#1Alan L. Ho (Cornell University)H-Index: 36
#2Irene BranaH-Index: 27
Last. Antonio GualbertoH-Index: 23
view all 25 authors...
PURPOSEMutations in the HRAS (mHRAS) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransfer...
#1Rohan Chippalkatti (University of Luxembourg)H-Index: 1
#2Daniel Abankwa (University of Luxembourg)H-Index: 21
Cancer stem cells (CSC) may be the most relevant and elusive cancer cell population, as they have the exquisite ability to seed new tumors. It is plausible, that highly mutated cancer genes, such as KRAS, are functionally associated with processes contributing to the emergence of stemness traits. In this review, we will summarize the evidence for a stemness driving activity of oncogenic Ras. This activity appears to differ by Ras isoform, with the highly mutated KRAS having a particularly profou...
#1Fiona M Healy (University of Liverpool)
#2Ian A. Prior (University of Liverpool)H-Index: 49
Last. David J. MacEwan (University of Liverpool)H-Index: 41
view all 3 authors...
In this review, we analyse the impact of oncogenic Ras mutations in mediating cancer drug resistance, and progress made in the abrogation of this resistance, through pharmacological targeting. At a physiological level, Ras is implicated in many cellular proliferation and survival pathways. However, mutations within this small GTPase can be responsible for the initiation of cancer, therapeutic resistance and failure and ultimately disease relapse. Often termed 'undruggable', Ras is notoriously di...
#1Tobias Sinnberg (University of Tübingen)H-Index: 22
Last. Lukas FlatzH-Index: 25
view all 24 authors...
Complications affecting the lung are hallmarks of severe coronavirus disease 2019 (COVID-19). While there is evidence for autoimmunity in severe COVID-19, the exact mechanisms remain unknown. Here, we established a prospective observational cohort to study lung specific autoantibodies (auto-Abs). Incubation of plasma from severe COVID-19 patients with healthy human lung tissue revealed the presence of IgA antibodies binding to surfactant-producing pneumocytes. Enzyme-linked immunosorbent assays ...
#1Saima UsmanH-Index: 2
Last. Ahmad WaseemH-Index: 24
view all 4 authors...
Oral cancer is a sub-category of head and neck cancers that initiates in the oral cavity. The primary treatment option for oral cancer remained surgery but it is associated with major disfigurement, inability to carryout normal oral functions, psycho-social stress and exhaustive rehabilitation. Chemotherapy is another treatment option that has limitations in terms of toxicity, intolerability, development of resistance to the chemical agents and non-specificity. Radiotherapy alone or in combinati...
#1Renata TisiH-Index: 15
#2Michela Spinelli (University of Milan)H-Index: 2
Last. Elena SaccoH-Index: 11
view all 14 authors...
Ras oncoproteins play a crucial role in the onset, maintenance, and progression of the most common and deadly human cancers. Despite extensive research efforts, only few mutant-specific Ras inhibitors have been reported. We show that cmp4 – previously identified as a water-soluble Ras inhibitor– targets multiple steps in the activation and downstream signaling of different Ras mutants and isoforms. Binding of this pan-Ras inhibitor to an extended Switch II pocket on HRas and KRas proteins induce...