NRAS G12S

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.

These findings argue against the development of 'early' resistance mechanisms after neratinib and pemetrexed exposure. Future studies will be required to understand how NSCLC cells become resistant to neratinib and pemetrexed.

Conclusions Molecular screening in non-BRAF PTC patients is useful to identify patients harboring RET fusions who may benefit from targeted therapies. As other potentially actionable gene fusions are also found in these patients, routine implementation of NGS analysis warrants a comprehensive biomarker study.

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.

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.

P1/2, N=156, Recruiting, Elicio Therapeutics | Not yet recruiting --> Recruiting

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

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.

We tracked clonal dynamics over time and detected the emergence of high-risk CTC subclones. Our findings show that capture and genomic profiling of CTCs could be a robust surrogate for BM biopsy, allowing minimally invasive detection and monitoring of disease and unlocking the clinical potential of liquid biopsies for MM diagnostics.

The combination of milademetan and trametinib demonstrated synergy in vitro and combinatorial superiority in vivo. These data support the exploration of combination of milademetan and MAPK inhibition in patients whose tumors harbor selected genetic alterations, including MDM2 amplification, CDKN2A loss or WT TP53.

Immunophenotypic analysis, clonality test, and targeted gene sequencing along with clinicoradiologic evaluation, may be helpful for establishing the diagnosis of T-PCNSL. Moreover, this study demonstrates genetic alterations with potential diagnostic and therapeutic utility in T-PCNSL.

The Myeloproliferative Neoplasm Diagnostic Assay on the Genexus system provides a comprehensive and rapid solution for molecular diagnosis of MPNs. Careful examination of all filters and IGV sequence analysis are required to reduce false negatives, especially in CALR gene. Secondary confirmation may be necessary for CALR mutations appearing as “No Call” in the “No Filter” setting.

PDAC studies were done in RAS-mutant (7 KRAS, 1 NRAS) patient derived xenograft (PDX) models, and Panc-1 (KRAS-G12D) cells and xenografts +/- gemcitabine (Gem). NSCLC studies were done in A549 (KRAS G12S) cells and xenografts, and ST2972 (KRAS G12C) PDX tumors +/- docetaxel (Doc). In RAS-mutant PDAC PDX models derived from previously treated patients, SA SY-5609 (6mpk QD x28) induced regressions in 50% (4/8) of models and was well-tolerated (average body weight change [avg-BWC] 0%); regressions were sustained ≥2 weeks (wks) after drug discontinuation... SY-5609 shows robust antitumor activity in RAS-mutant PDAC and NSCLC preclinical models. support clinical evaluation of SY-5609 in combination with Gem in PDAC and Doc in NSCLC.

We performed additional mechanistic analyses to redefine neratinib biology and determined the mechanisms by which the multi-kinase inhibitor neratinib interacted with the thymidylate synthase inhibitor pemetrexed to kill NSCLC cells expressing either mutant KRAS (G12S; Q61H; G12A; G12C) or mutant NRAS (Q61K) or mutant ERBB1 (L858R; L858R T790M; exon 19 deletion)...Afatinib or osimertinib resistant cells were killed with a similar efficacy to non-resistant cells...Thus, neratinib targets an unidentified protein whose functional inhibition directly results in RAS inactivation and tumor cell killing. Our data prove that, albeit indirectly, oncogenic RAS proteins are druggable by neratinib.

Results In comparison to parental, the SUP-B15 IR, DR and PR cell lines were resistant to all TKIs (imatinib, nilotinib, dasatinib and ponatinib) and to asciminib...Whilst these cell lines were resistant to the Mcl-1‐selective inhibitor S63845 (LD50=290 nM vs 78.5 nM for parental), combination therapy with venetoclax was synergistic in overcoming resistance (CI=0.051 for 50 nM S63845 and 5 nM venetoclax)...The DRKRASmut and PRNRASmut lines instead showed overexpression of Bcl-2 (P=0.0079 and P=0.01 respectively), but not pBCR-ABL or Mcl-1, which could explain why venetoclax alone overcame resistance in these cell lines Conclusion Combination therapy of TKIs and venetoclax could be promising for Ph+ ALL patients carrying PTPN11 mutations and Mcl-1 overexpression. Studies are ongoing to determine the role of the mutations in PTPN11 in the development of the resistance.

The tumor showed no response to sorafenib...Here, this was the first evidence that the mosaic KRAS G12S mutation, but not acquired mutation, resulted in a poorer prognosis of BRAF mutant PTC patient with dabrafenib and trametinib treatment: only 5 months of response in this patient, while 12.6 months of median duration of response in BRF113928 clinical trial of this combo strategy. This was the first report that mosaic KRAS G12S mutation was associated with cancer, and it was also the first report of mosaicism in thyroid tumor. This was the first report that mosaic KRAS G12S mutation was associated with cancer, and it was also the first report of mosaicism in thyroid tumor. We speculated that mosaic KRAS G12S mutation was one of the factors leading to more malignant tumor and rapid disease progression. These results suggest that it is important to pay attention to mosaic mutations when detecting the somatic mutations of tumor.

This comprehensive RNAbased NGS panel reliably identified fusions, exon skipping, and SNVs in a wide spectrum of myeloid and lymphoid malignancies including Ph-like ALL. The ability of this assay to simultaneously detect RNA and DNA aberrations simplifies the workflow, is cost-effective, and most importantly, more efficiently and effectively guides clinical management of our patients.

Elucidation of differential effector engagement responsible for the variable phenotypic readouts of the mutants is warranted. If validated by mouse studies and clinical correlates, these can have wider implications in choosing treatment options.

We show that mutant KRAS is a negative prognostic factor and that p.G12C/p.G12S variants present the worst clinical courses. This information suggests a clear difference among KRAS mutations, and it will be useful to test potentiated and/or innovative therapeutic strategies in p.G12C/p.G12S metastatic CRC patients.

Legal entity responsible for the study The author. Funding Has not received any funding.

Our data demonstrated that HL-085 is well tolerated, with manageable side-effects and promising anti-cancer activity in pts with NRASm advanced melanoma. Research Funding: Shanghai KeChow Pharma