HRAS wild-type

Compared to HSCDA Proficient mice, tumors from HSCDA Deficient mice showed reduced densities of dendritic cells (DC) and natural killer (NK) cells, as well as fewer DCs, NKs, and B-cells in proximity to tumor cells, as determined by spatial analysis. Overall, our data suggest that HSCDAs promote HGSC survival and plasticity while downregulating expression of tumor suppressors and altering the peritoneal immune and metabolic environment to promote HGSC progression.

Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival, further confirming the accuracy and reliability of the model. Based on protein-protein interaction (PPI) network and RNA sequencing analyses, we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis, with subsequent progression to HCC. Collectively, our study successfully duplicated natural sequential progression in a single murine model over a very short period, providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC)...Finally, HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16-2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRASmt tumors that may help to identify new targets and guide future clinical trial design.

Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

Combination treatment of regorafenib plus FOLFIRI with dose-escalated irinotecan according to UGT1A1genotyping results in a significant better PFS and comparable AEs. Moreover, patients with RAS wild type of CRC would be more beneficial for this combination treatment.

Moreover, increased area occupied by CD11c+ dendritic cells and numbers of CD8+ T cells were found in regional lymph nodes from HRAS mutant patients (79.25% vs 38.80%, p=0.036 and 10160.43 vs 4438.28/mm2, p=0.036, respectively), consistent with data showing that maintenance of TCF1 by intratumoral T cells requires continuous migration from draining lymph nodes. Conclusions Pre-exhausted PD-1(+)TCF-1(+) T cells are significantly increased at the periphery of HRAS mutant tumors, suggesting a potential sensitivity of these tumors to ICB.

Recently, several preclinical and clinical advancements have been made in the implementation of small-molecule inhibitors that block post-translational farnesylation of HRas, thereby abrogating its downstream oncogenic activity. In this review, we focus on the biology of wild-type and mutant HRas signaling in HNSCC, and rationale for use and outcomes of farnesyltransferase inhibitors in patients with HRAS-mutant tumors.

In the N-nitroso-N-methylurea-induced ER positive rat breast model (50%HRAS mutations) various selective estrogen receptor modulators, aromatase inhibitors, epidermal growth factor receptor inhibitors, and retinoid X receptor agonists are profoundly effective in prevention and interception of tumors with wild type or mutant HRAS, while the farnesyltransferase inhibitor tipifarnib preferentially inhibits HRAS-mutant breast tumors. Thus, many agents not known to specifically inhibit the RAS pathway, are effective in an organ specific manner in preventing or intercepting RAS-mutated tumors. Finally, we discuss an alternative prevention and interception approach, employing vaccines to target KRAS.

P2, N=284, Active, not recruiting, Kura Oncology, Inc. | Recruiting --> Active, not recruiting | Trial completion date: May 2022 --> May 2023 | Trial primary completion date: May 2021 --> May 2023

Our transcriptomic analysis suggests HRAS-Q61 mutations were associated with lower response to immunotherapy and leads to MAPK activation, as well as modulation of important TME pathways, possibly indicating a distinct biological and clinical phenotype. Our study provides rationale for therapeutic HRAS targeting in UBC.

HRAS mutant HNSCC are associated with high PD-L1 expression and co-occurrence of p53 mutations. Combinations of tipifarnib with an anti-PD1 antibody, an anti-PDL1 antibody, or an anti-CTLA-4 antibody warrant clinical investigation in this rare subset of HNSCC.

All observed/available data among each cohort will be evaluated before choosing the combination dose for a subsequent cohort. The trial opened for enrollment in October 2021.