NRAS G13

Accurate pathological diagnosis is prognostically valuable. The histological features of enteroblastic differentiation, elevated serum AFP levels, and the expression of oncofetal proteins play an important role in the tumor diagnosis.

See also the graphical abstract(Fig. 1).

Tunlametinib showed promising antitumor activity with a manageable safety profile in patients with advanced NRAS-mutant melanoma, including those who had prior exposure to immunotherapy. The findings warrant further validation in a randomized clinical trial.

Therefore, the seven SNPs were identified as high-risk SNPs. Conclusions Given that SNPs have the potential to be candidates for cellular alterations brought on by mutations that are associated with cancer, this study provides vital information about how SNPs might be utilized as a diagnostic marker for cancer.

The anti-tumor effects of LY3009120 were observed in nine melanoma cell lines, indicating the potential feasibility of experimental trials with LY3009120. The present study reveals that the irradiation-resistant canine metastasis cells (cRGO1.2) harboring the NRAS p.G13R mutation are significantly LY3009120-sensitive, while the equine metastases-derived eRGO6 cells show significant resistance to LY3009120, which make them both valuable tools for studying resistance mechanisms in comparative oncology.

Here, we demonstrate that the "young" ddPCR technology is as effective as a CE-IVD marked real-time PCR method for detecting BRAF V600 hotspot mutations in tumor biopsies and recommend it for extended use in clinical settings. Moreover, ddPCR was able to detect low-frequency hotspot mutations, such as NRAS G12/G13, in our tissue specimens, which makes it a promising tool for investigating the mutational landscape of sun-damaged skin, benign nevi, and melanomas in more extensive clinical studies.

P2, N=34, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025

Conclusions NGS-ctDNA provided clinically informative results for 26% of pts with advanced lung SCC, including 6% for whom targeted therapies are available in routine practice or clinical trials (4% ESMO ESCAT tier I and 2% ESMO ESCAT tier IIB). These results suggest that molecular profiling, including plasma NGS testing, should be considered in this population.

P1, N=120, Recruiting, InxMed (Shanghai) Co., Ltd. | Trial completion date: Jun 2024 --> Sep 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

We demonstrate that RNA-seq is an effective tool for precision medicine in B-ALL by providing comprehensive molecular profiling of leukemia cells, identifying subtype and oncogenic lesions, and stratifying patients for appropriate therapy.

The circulating VAF of RAS genes enables to split RAS mutant-Low (favorable prognosis similar to RAS/BRAF wild-type) from RAS mutant-High (poorer prognosis similar to BRAF mutant) metastatic colorectal cancer. These results provide further insights into prognostication and therapeutic strategies in patients with RAS mutant metastatic colorectal cancer.

These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi.

Some SMO inhibitors have been tested in clinical trial and Glasdegib is FDA approved in combination with low dose cytarabine in elderly patients. Given the success of generating these two point mutations, we are currently generating more RAS pathway mutations, including other KRAS mutations, PNTP11 and NF1 mutations. Conclusion These experiments showed: 1) It is possible to induce 2 oncogenic hits in human primary cells and get leukemia in vivo; 2) the KRAS G13D and NRAS G12D mutations shorten the latency of the disease and 3) increase the LSC frequency in secondary mice; 4) a possible involvement of the Hh pathway on stemness/LSC in RAS mutated cells; 5) our experimental approach is robust and very promising to decipher the RAS pathway in human MLL leukemias.

We further revealed a distinct mutation profile between AMKL and non-AMKL and shed light on association between driver aberrations and clinical outcomes. These findings revealed non-DS-AMKL as a heterogenous disease, and suggested the importance of exploration of risk-stratification and targeted therapy in different mutations driven cases.

The "clonal attack" by DDR inhibitors shifts the paradigm of genotoxic therapies from those using non-discriminative cytotoxic drugs to those selectively attacking DDR vulnerabilities in AML clones with minimal harm to normal cells. Since clonal heterogeneity and DNA damage are hallmarks of cancer, the "clonal attack" may be broadly applicable to the quest for cancer cure.

In addition to well-characterized MM drivers (KRAS, NRAS, etc.), 16 new candidate genes were found significantly mutated, including IKFZ3 (Aiolos), a transcription factor and direct target of degradation with lenalidomide therapy, harboring frameshift and stop-gain mutations in the protein dimerization domain which could affect complete differentiation of plasma cells...Conclusion These results highlight the power of genomic profiling in MM for early detection, discovery of novel drivers, monitoring of clonal selection and transformation to malignant disease. We show SMM is not a simple genomically-mature disorder, but rather a dynamic state with competing subclones, which could be leveraged for therapeutic interventions.

Through deep transcriptomic characterization combined with conventional diagnostics, this analysis uncovered novel mechanisms of VEN resistance while confirming established ones. The distinct gene expression patterns may help tailor targeted therapies, with patients showing the "activating-like" signature potentially benefiting from tyrosine kinase inhibitors and those with the "self-renewal like" signature possibly responding well to histone deacetylase inhibitors. Furthermore, HOXA gene overexpression presents an exciting therapeutic opportunity for selected patients.

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.

We also revealed a correlation between tumor-infiltrating immune cells in RAS mutated AML microenvironment. Our findings suggest that DUSP1 signaling pathways may regulate Ara-C sensitivity in AML.

All 4 cancer-specific VTE models exhibit moderate performance when identifying mCRC patients at high risk of VTE. Incorporating KRAS and BRAF mutations may enhance the prediction of VTE in hospitalized mCRC patients.

The MAPK DM, high TMB and persistent genomic instability suggest roles for MAPK-targeted therapies, immunotherapies and DNA damage repair pathway inhibitors, respectively, in EMD. Recurrent codon 61 mutations in RAS suggest a specific role in EMD progression.

The mutational profile of HR SMM patients is similar to symptomatic MM. If validated in larger studies, t(4; 14) plus FGFR3 mutations, or NRAS mutations, could be used to predict resistance and a shorter time to disease progression.

NGS-based molecular testing provides useful insights about molecular signatures of these nodules/cancers. Widespread adoption of genetic testing will help establish diagnostic sensitivity and specificity for this panel. Molecular Characterization of Thyroid Nodules—Correlation With Histopathology

P1; Recruiting --> Active, not recruiting | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

The identification of targetable genomic alterations in tumors from individuals living with HIV and solid organ transplant recipients underscores the importance of comprehensive molecular testing in these patient populations. While important markers of immunotherapy response (PD-L1, TMB) were similar, different immune characteristics were identified. Further research is necessary to fully understand the molecular profiles of lung cancer in individuals with HIV and solid organ transplant.

Neo-adjuvant Ipilimumab and Nivolumab treatment was soon initiated...This leads us to believe that CHEK2 mutant AMM patients, could benefit from new treatment strategies such as PARP inhibitors and epirubicin, that have already shown promising results in CHEK2 mutant breast and pancreatic cancer patients...Nonetheless, the identification of individuals carrying CHEK2 mutations is still crucial, as it may enable their tailored surveillance leading to an early detection of melanoma or other associated tumors . Moreover, it could possibly allow refractory melanoma cases to benefit from treatment strategies that target CHEK2 specifically, enhancing this way melanoma cell treatment sensitivity to treatment.

Our results demonstrate higher expression of CHIP in COVID19 pts (27.9%), with increased risk of TE, namely in those pts carrying mutations including DAT pathway genes. This may help in early detection of pts at risk, to prevent severe complications and reduce mortality. CHIP, Pulmonary embolism, Thrombosis, COVID-19

In this cohort with population-based and real-world patients, no differences in patient characteristics or treatment modalities were seen between different RAS mt, except a higher frequency of right-colon primaries among KRAS mt compared with NRAS mt. KRAS -G12S conferred a worse OS compared with some other KRAS mt, whereas no other differences in OS were seen. It therefore seems as if different RAS mt behave quite similar.

Our results highlighted a difference in the molecular profile of KRAS, NRAS,and BRAF mutations' distribution between metastatic colorectal cancer and non-metastatic ones: NRAS and BRAF mutations were associated with metastasis advent; moreover, the G13D mutation of KRAS was correlated to a better prognosis than mutations in codon 12 of KRAS: G12A and G12S alleles gave the worst prognosis.

In a 3+3 dose escalation, n=22 received a subcutaneous course of 6 prime and 4 booster injections of fixed dose Amph-peptides (1.4 mg), admixed with escalating Amph-CpG-7909 (Table). ELI-002 2P, evaluated in a novel MRD+ trial, was safe with ctDNA and serum tumor biomarker reduction and clearance and notable immune responses. The RP2D is the start dose for a phase 1/randomized phase 2 study evaluating a new seven peptide formulation for G12 D, R, V, S, A, C, and G13D mutated solid tumors (NCT05726864). Clinical trial information: NCT04853017.

P2 | "According to liquid biopsy before second- and third-line therapies, treatment sequences are: FOLFIRI + cetuximab (first-line), FOLFOX + cetuximab (second-line); irinotecan + cetuximab (third-line) in patients with plasma ctDNA RAS/BRAFV600E WT tumors. In patients with RAS/BRAFV600E mutant tumors, second-line is FOLFOX + bevacizumab, while third-line is regorafenib or trifluridine/tipiracil (investigator's choice)... Both tumor tissue- and liquid biopsy-based comprehensive genomic profiling by NGS identify additional molecular alterations, that could be involved in resistance to anti-EGFR monoclonal antibodies, as compared to PCR-based tumor tissue analysis. CAPRI 2-GOIM trial will determine if NGS would allow better selection of RAS/BRAFV600E WT mCRC patients for the most appropriate treatments through three sequential lines of therapies."

P1/2, N=37, Terminated, Haihe Biopharma Co., Ltd. | N=150 --> 37 | Trial completion date: Dec 2024 --> Mar 2023 | Recruiting --> Terminated | Trial primary completion date: Dec 2023 --> Mar 2023; Sponsor business decision

Our real-world data, single centre 5-year analysis showed that the distribution between wild type and mutated type tumors of the patients with mCRC was approximately the same, as worldwide, so the Slovenian population with mCRC has the same ratio distribution of KRAS, NRAS and BRAF wild and mutated genes. We concluded that a two-week waiting period for biomarkers analysis did not influence the first line treatment decision, so it was in the accordance with the worldwide treatment guidelines based on evidence-based medicine.

MAPK DM were frequent in EMD, and detectable in ctDNA, suggesting roles for both MAPK-targeted therapies and for ctDNA as a biomarker in these patients. A high TMB was identified in patients lacking a MAPK driver mutation; immunotherapy should be considered in this subgroup.

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=156, Recruiting, Elicio Therapeutics | Not yet recruiting --> Recruiting

P2, N=34, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2023 --> Jan 2024

P1/2, N=156, Not yet recruiting, Elicio Therapeutics

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.

Our study demonstrated the clinical relevance of minor mutant subclones in EGFR signaling pathway genes in plasma for predicting response to anti-EGFR treatment. Although sample size of this study was small, preferable threshold for distinguishing responders from non-responders may be 0.5% as VAF of these gene mutations. Clinical trial information: 000034923.

Beside established anti-CRC treatment, better understanding of the causality of CRC can be established by combining epidemiology and genetic/epigenetic on CRC etiology in Morocco. This approach may be able to significantly reduce the burden of disease in the country. Moreover, the Moroccan government should develop policy on CRC prevention and public health programs which may serve as a feasible setting to increase public awareness on lifestyle risk factors.