NRAS Q61L

However, parity decreased the overall prevalence of tumors bearing Krasmut, and the magnitude of this decrease depended on both the number and timing of pregnancies. These multistage models may be useful for elucidating biological features of premalignant mammary neoplasia.

Additionally, CT2A-luc demonstrated substantial baseline secretion of the CCL-2, CCL-5, and CCL-22 chemokines, which play important roles as myeloid chemoattractants. Although the clinical contexts that can be modeled by GL261 and CT2A for huGBM are limited, CT2A may be an informative model of immunotherapy resistance due to its deficits in antigen presentation machinery and interferon response pathways.

RMC-7977 is a potent, oral small molecule inhibitor of both wild-type and mutant GTP-bound RAS oncoproteins (RASMULTI) and is a preclinical tool compound representative of the clinical candidate RMC-6236, currently in clinical evaluation (NCT05379985)...Gilteritinib and the gilteritinib/venetoclax combination selected for survival of cells harboring NRAS mutations, but RMC-7977 inhibited outgrowth of all cell populations...In vivo studies investigating the tolerability and activity of RMC-7977 and RMC-7977 combinations in RAS mutant/FLT3i-resistant patient-derived xenograft models are ongoing and will be presented. Collectively, our data provide preclinical evidence that combination therapies leveraging RASMULTI(ON) inhibition are effective in suppressing RAS-mutant AML clones, a common mechanism of resistance to currently approved targeted therapies in AML and a current area of high unmet clinical need.

Primary limitations include the total quantity of single cells and breadth of available genomic subtypes plus inherent noisiness of the applied methodologies. Nonetheless, these findings nominate novel, testable therapeutic targets.

We found that all 23 CAAs showed diffuse and strong membranous RAS Q61R immunoreactivity (100% sensitivity), while none of the 8 OSCCs showed immunoreactivity (100% specificity). The data supports the use of RAS Q61R-specific rabbit monoclonal antibody for diagnostic IHC confirmation of CAA and ruling out OSCC in dogs.

Even focal expression of a melanocytic marker should cast doubt on a diagnosis of PDS and raise the possibility of de-differentiated melanoma, since therapy and outcomes are significantly different. Poster type: Poster Defense

P1/2, N=39, Completed, Gritstone bio, Inc. | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Mar 2023 | Trial primary completion date: Dec 2023 --> Mar 2023

Each OSUMMER cell line possesses distinct in vitro growth properties, trametinib sensitivity, mutational signatures, and predicted antigenicity. Analysis of OSUMMER allografts shows a correlation between strong, predicted antigenicity and poor tumor outgrowth. These data suggest that the OSUMMER lines will be a valuable tool for modeling the heterogeneous responses of human melanomas to targeted and immune-based therapies.

Regimen was switched to oral Binimetinib 45 mg daily for advanced NRAS mutant melanoma...Immune checkpoint inhibitors Pembrolizumab, Ipilimumab and Nivolumab are the most common immunotherapeutic agents used for mucosal melanomas. More recently Talimogene Laherparepvec (T-VEC) intra-lesional therapy is used to invoke local immune response which has promising results. Rapid progression of mucosal melanomas require early detection and intervention to prevent metastasis and recurrence however overall survival rate is not affected.

NRAS mutated melanoma has been shown to respond to treatment with the MEK-inhibitor binimetinib, however the PFS of 2,8 months and the median OS of 11 months was not promising [1]. Three patients with high tumor load all benefitted from treatment with trametinib and showed a explicitly longer PFS than the published data. After progression on ICB we therefore recommend to consider MEK-inhibition for NRAS mutated melanoma in selected cases.

P2/3, N=8, Terminated, The Christie NHS Foundation Trust | N=1050 --> 8 | Trial completion date: Oct 2030 --> Jan 2023 | Recruiting --> Terminated | Trial primary completion date: Oct 2030 --> Jan 2023; Closed earlier than expected due to the need for a redesign to reflect the recent change in standard of care guidelines. New design will include these treatments.

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.

"Of 21 pts with paired plasma samples, 17 (81%) had ≥1 acquired genomic alteration. RTK alterations and secondary (2°) RAS alterations were most common; each occurred in 57% of pts (Table). KRAS amplification was the most common single alteration (43%)."

Additionally, CT2A-luc demonstrated substantial baseline secretion of the CCL-2, CCL-5, and CCL-22 chemokines, all of which are known to play important roles as myeloid chemoattractants, in marked contrast to GL261-luc2.The defect in MHC class I expression could be overcome in CT2A-luc by interferon-γ treatment, which may underlie the modest efficacy of some immunotherapy combinations for CT2A-luc. Thus, CT2A-luc may be an informative preclinical model of immunotherapy resistance due to its mesenchymal differentiation and antigen presentation machinery deficits.

We therefore anticipate mechanistic analyses of how %VAF and drug timing can optimize counter-resistance therapies. Overall, our interim data suggest a significant percentage of metastatic BRAF-mutated melanoma patients may harbor pre-existing resistant subclones, and that early treatment with counter-resistance therapy can potentially delay resistance to targeted therapy.

P1/2, N=39, Active, not recruiting, Gritstone bio, Inc. | Recruiting --> Active, not recruiting | N=144 --> 39

P1/2, N=144, Recruiting, Gritstone bio, Inc. | Trial primary completion date: Dec 2022 --> Dec 2023

Recognizing and referring patients with possible germline mutations for appropriate genetic evaluation and testing provides insight into best patient care strategies along with education and testing opportunities for family members. Leukemia based NGS panels may aid as screening tools for detecting potential pathogenic germline variants.

RAS mutations could be useful in future target anti-EGFR therapy and molecular CRC screening strategy in Morocco.

KRAS mutated CRC patients in North Africa have been identified with incidence closer to the European figures. Beside established anti-CRC treatment, better understanding of the causality of CRC can be established by combining epidemiology and genetic/epigenetic on CRC etiology. This approach may be able to significantly reduce the burden of CRC in North Africa.

"The 23 common mutations detected in the BRAF and NRAS genes using this assay have significant impact on therapeutic selection. Somatic variants in the BRAF gene have been found in 37%-50% of all malignant melanomas, whereas somatic variants in the NRAS gene are found in 13%-25% of all melanomas. The Biocartis Idylla system offers a simple and rapid method to obtain somatic mutation information in these two genes that are of clinical importance."

HRAS mutation, a well-known genetic alteration of low-grade tumor in bladder cancer, was detected only in the high-grade UTUC in the public data, suggesting a rather distinct molecular alteration of UTUC. Also, HRAS alteration was clonally retained in not only the low-grade but also the high-grade components, and was significantly correlated to intratumoral heterogeneity. Our findings can help understand the underlying biology of NI-UTUC cases with HRAS alteration and intratumoral heterogeneity.

These patients received various therapies including pembrolizumab, nivolumab, capmatinib, bevacizumab, osimertinib, brigatinib, erlotinib, and alectinib, as well as sotorasib. Collection and sequencing of RTD samples provides an opportunity to detect resistance mutations and to understand more about post-treatment disease progression and tumor heterogeneity. The identification of drivers by comprehensive NGS tissue testing in two cases serves as a reminder about the value of such testing when no drivers are identified by small panels or blood-based NGS testing.

Clinical molecular testing in our cohort revealed these gene alterations mainly in pediatric patients and enabled diagnosis, prognosis, and risk stratification allowing the use of clinically actionable therapeutic targets in some cases. It also contributed toward a useful data set for further analysis and potential for novel drug development. Longer-term followup incorporating therapy and outcomes information would be valuable.

Multiple genetic alterations are associated with clinical benefits and resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC. Our findings provide novel insights into strategies for overcoming resistance to EGFR/BRAF inhibitors in patients with BRAF V600E-mutant mCRC.

Molecular dynamics simulations, combined with cell-based protein-protein interaction studies, reveal that melanomagenic NRAS mutants form intramolecular contacts that enhance BRAF binding affinity, BRAF-CRAF heterodimer formation, and MAPK > ERK signaling. Along with the allelic series of conditional mouse models we describe, these results establish a mechanistic basis for the enrichment of specific NRAS mutants in human melanoma.

The clinical course of patients with HRAS-mutant NSCLC remains unclear. Furthers cases should be identified in order to clarify prognosis and response to therapies. Tipifarnib, a farnesyl transferase inhibitor, is a promising candidate to target HRAS-mutant tumours and should be explored in NSCLC patients.

In our retrospective study we found that among stage III BRAF-mutant patients monotherapy with aPD1 was the most common adjuvant treatment regimen. In some patients with stage III disease IFN-alfa is still given. More studies are needed to define best adjuvant treatment for BRAF mutant stage III melanoma pts.

In contrast to cancer arising from the thyroid gland, characterized by BRAFV600E as the most common mutation, malignant SO belongs to RAS-like tumors. The downregulation of tumor suppressors and upregulation of DMRT1 might be implicated in the malignant transformation of SO.

P2/3, N=1050, Recruiting, The Christie NHS Foundation Trust | Not yet recruiting --> Recruiting

Clinical molecular testing in our patients revealed gene alterations that provide refinement of diagnosis, prognosis, and risk stratification allowing the use of clinically actionable therapeutic targets in some cases. It also contributes toward a useful data set for further analysis and impactful targeted management. Longer-term follow-up incorporating therapy and outcomes information would be valuable.

High resolution NMR data allowed the unambiguous assignments of H-N correlation cross-peaks for all the residues except for Met1. Furthermore, 2D H-N HSQC overlay of two proteins assisted in determination of Q61L mutation-induced chemical shift perturbations for select residues in the regions of P-loop, Switch-II, and helix α3.

P2/3, N=1050, Not yet recruiting, The Christie NHS Foundation Trust | Initiation date: Jun 2021 --> Sep 2021

We demonstrated that composite PCC/PGL-GN might be a unique entity with frequent HRAS and BRAF mutations rather than genetic changes of SDH and ATRX. Our findings revealed the possible pathogenesis of composite PCC/PGL-GN and provided clues for potential treatment targets.

Our findings suggest that a BRAF and NRAS developed co-mutation may lead to a distinct clinicopathological progression. BRAF-mutated CRCwill not benefit from anti-RAS targeted therapy.