HRAS G12S

This validated phenotypic characterization of a large number of patients with CS will allow future researchers to make a positive diagnosis, and to differentiate CS from CFCS and NS.

Lastly, in HRAS-mutated PDXs and in the syngeneic HRAS model, we demonstrated that tipifarnib efficacy is limited by activation of the AKT pathway, and dual treatment with tipifarnib and the PI3K inhibitor, BYL719, resulted in enhanced anti-tumor efficacy. Our case study highlights the potential of targeting HRAS mutations with tipifarnib in R/M HNSCC and identifies potential mechanisms of acquired resistance to tipifarnib, along with immuno-, chemo-, and radiation therapy. Preclinical results provide a firm foundation for further investigation of drug combinations of HRAS-and PI3K -targeting therapeutics in R/M HRAS-driven HNSCC.

Our findings suggest that KRAS may be mutated more frequently in OSCC compared to HRAS and NRAS. Also, the histological features of nuclear and cellular diameter differed significantly between the KRAS mutated and unmutated cases.

Oncogenic mutations in HRAS occur in 3%-4% of HNSCC, with G12S being the most frequent. Without targeted therapy, patients with HRAS-mutant HNSCC had poor clinic outcomes; observable trend toward improvement in OS has been noted in cohorts receiving treatments such as tipifarnib. The comutation pattern of HRAS-mutant in HNSCC is distinct, which may provide insight to future therapeutic combination strategies.

This validation study supports the feasibility of applying NGS testing to leftover fixed urine cytology specimens. In addition, the potential utility of urine NGS testing as an adjunct to urine cytology in the early detection of HGUC for cases in which cytology is negative and/or atypical/suspicious should be investigated further.

The metastasis-derived PDX was treated in vivo by different chemotherapies and a combination of MEK and BRAF inhibitors (trametinib and dabrafenib). Treatment of the PDX by the MEK inhibitor trametinib, resulted in a marked anti-tumor activity, in contrast to the BRAF inhibitor and the different chemotherapies that were ineffective. Overall, these findings further expand on the genetic features of AMEs and suggest that patients carrying advanced HRAS-mutated AMEs could potentially be treated with MEK inhibitors.

These findings demonstrate that genetic risk of RMS results from germline predisposition variants associated with a wide spectrum of cancer-susceptibility syndromes. Germline genetic testing for children with RMS should be informed by RMS subtypes and not be limited to only young patients.

Oral tipifarnib resulted in manageable safety profile and encouraging antitumor efficacy against treatment-refractory UC containing HRAS mutations.