KRAS G13D

Furthermore, small-molecule RAS•SOS disruptors fail to dissociate KRASG13D•SOScat complexes, underscoring the need for more potent disruptors targeting oncogenic RAS mutants. Taken together, native MS will be instrumental in better understanding the interaction between oncogenic RAS mutants and SOS, which is of crucial importance for development of improved therapeutics.

Mechanistically, reorientation of KRAS4B G-domain exposes distinct residues, such as Arg 135 in orientation state 1 (OS1) and Arg 73/Arg 102 in OS2, to the PM and differentially facilitates the recognition of PS acyl chains...Distribution of these KRAS4B oncogenic mutants favors different nanoscale membrane topography. Thus, RAS G-domains allosterically facilitate membrane lateral distribution.

In the non-hypermutated CRC cohort, the prognostic risk of various RAS/BRAF allele mutations varied between local and metastatic CRC. KRAS G13D mutation tended to be the only prognostic marker for stages I-III CRC; however, KRAS G13D/G12V/G12C mutations collectively defined a high-risk subgroup of mCRC patients with poor prognosis, who would benefit from intensive triplet chemotherapy.

P1, N=12, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Apr 2026 --> Apr 2027 | Trial primary completion date: Apr 2024 --> Apr 2025

In this report, we describe the design and evaluation of potent and KRAS G13D-selective reversible inhibitors. Subnanomolar binding to the GDP state Switch II pocket and biochemical selectivity over WT KRAS are achieved by leveraging a salt bridge with D13.

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.

Patient backgrounds did not differ significantly in terms of age (median 61/63), sex (male 49%/48%), performance status (PS0 32%/32%), site of primary tumor (right 33%/32%), number of metastatic sites (3≤ 28%/23%), treatment regimen (doublet 90%/92%, triplet 3%/4%), or first line bevacizumab (yes 81%/79%)... The KRAS G12D mutation did not show a detrimental prognostic impact on PFS and OS compared to KRAS non-G12D mutations in patients with RAS-mutated mCRC.

This study sheds light on the role of PHRF1 in the invasion of colorectal cancer HCT116-p53 cells, which harbor the oncogenic KrasG13D mutation and lack p53. These findings provide novel insights regarding the role of PHRF1 in invasion by modulating SOX4 expression in colorectal cancer HCT116-p53 cells.

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.

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.

Our data show that an MS approach can be used to demonstrate which shared oncogene-derived neoepitopes are processed and presented by common HLA alleles, and those MS data can rapidly be used to develop TCRs against these common tumor-specific antigens. Although further characterization of these neoepitope-specific murine TCRs is required, ultimately, they have the potential to be used clinically for adoptive cell therapy.

We developed and validated a robust and highly sensitive universal KRAS G12X digital PCR assay suitable for the molecular monitoring of pancreatic cancer patients in cell-free DNA. The assay has potential to complement established serum protein tumor markers in clinical routine.

This study provides significant evidence of the role of acquired KRAS variants in the development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Our results contribute to the growing body of knowledge on the mutational profiles associated with resistance to epidermal growth factor receptor-tyrosine kinase inhibitor treatment. Furthermore, our study highlights the KRAS gene change as a significant mechanism of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

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

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

Although binding free energy analysis through the umbrella sampling approach suggested that the affinity of CSC01 with the switch II pocket of KRAS-G13D is moderate, our DFT analysis showed that the stable interaction of the compound might be facilitated by the existence of favorable molecular electrostatic potentials. Furthermore, based on ADMET predictions, CSC01 demonstrated a satisfactory drug likeness and toxicity profile, making it an exemplary candidate for consideration as a potential KRAS-G13D inhibitor.

These preclinical results indicate unique therapeutic vulnerabilities across allelic subgroups. RNA-sequencing and kinome profiling will allow us to further characterise these mutations in NSCLC.

Eligible pts had disease progression after a 1L oxaliplatin-containing regimen...There is a high unmet need for a safe and combinable oral pan-RASm therapy in mCRC. Recruitment of RASm pts continues and a randomized controlled trial in 2L RASm mCRC is planned.

In addition, we evaluated the inhibition of tumor growth and metastasis by erianin in vivo using a subcutaneous tumor model and a spleen-liver metastasis model, respectively. Collectively, these data provide novel insights into the anticancer activity of erianin, which is valuable for the further discussion and investigation of the use of erianin in clinical anticancer chemotherapy for KRAS CRC.

The prevalence of the KRAS G13D mutation was significantly higher in patients with AR, and KRAS G13D-mutant patients with AR had a poorer prognosis than those that were negative for the KRAS G13D mutation. In conclusion, postoperative surveillance and treatment strategies should be considered with attention to the possibility of AR and subsequent recurrence in KRAS G13D-mutant patients.

These results demonstrated that non-engineered T cells with KRAS mutated-specific anticancer activity are an ideal candidate for KRAS mutant cancer-targeted immunotherapy. Further studies are necessary to verify the anticancer effects in vivo.

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

P1, N=12, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

The NGS panel could successfully detect actionable mutations in liquid biopsies with a high concordance rate and sensitivity. The detection of variants in cfDNA, but not in tDNA, suggests a greater representativeness of the mutational tumor spectrum in samples of liquid biopsies opening perspectives for employing this approach in the routing setting. The NGS assay for liquid biopsy may decrease tissue biopsies and turnaround time for report release, accelerating therapeutic strategies for NSCLC patients.

P2, N=28, Not yet recruiting, Tiziana Life Sciences LTD

After 6 courses of FOLFOXIRI with Cetuximab instead of Bevacizumab staging showed regressive metastases...After no response to Lonsurf + Bevacizumab the patient died 12 month after diagnosis. It seems remarkable that in primary chemotherapy-resistant mCRC with KRAS G13D mutation simply by switching antibody therapy, tumor response could be achieved. Switching antibody therapy may be considered for 2 nd line treatment.

Interestingly, the KRAS G13D isogenic line displays elevated PD-L1 expression suggesting the KRAS G13D mutation could be a potential indication for immunotherapy. Overall, these three novel isogenic cell models with endogenous level RAS and MEK1 point mutations provide direct bio-functional evidence demonstrating that acquiring a drug-resistant gene drives tumor cell survival and may simultaneously introduce new indications for combo therapy or immunotherapy in the clinic.

NTRK1, NTRK2, and NTRK3 fusions are clinically relevant driver alterations across solid tumor types. These fusions are difficult to detect, as the breakpoints occur across large intronic regions and they have many partner genes, with 10 novel fusion partners identified in this study. These data emphasize how important CGP with RNA sequencing is to identify all NTRK fusions for optimal patient treatment.

P3 | "All received adjuvant 5-Fluorouracil-based chemotherapy...A third patient with late recurrence did not have detectable ctDNA. Analyses in the larger cohort (n=368) are underway."

Although the efficacy of IL1RAP CAR-T cells in murine EwS xenografts was limited by an immune suppressive tumor microenvironment, the anti-IL1RAP ADCs effectively limited EwS tumor progression at low doses such as 0.1mg/kg. Conclusions Therefore, we have defined surface IL1RAP as an immunotherapy target in EwS and potentially other human malignancies, and our pre-clinical studies suggest anti-IL1RAP ADCs as a highly promising immunotherapy strategy.

A comparison of isogenic SW48 xenografts with different KRAS mutations confirmed that KRASG13D/+ (followed by G12V/+) mutations are especially sensitive to 249C treatment. These data establish proof-of-concept for targeting V-ATPase in cancers driven by specific KRAS mutations such as KRASG13D and G12V.

Experimental anti-tumour Benzoprims, analogues of the anti-malarial drug pyrimethamine, possess anti-tumour activity against metastatic melanoma cells, mainly by inhibiting dihydrofolate reductase (DHFR), a validated target in cancer therapy...Conclusion Benzoprims are most potent in CRC cell lines possessing mutant KRAS G13D . Although their mechanism of action independent of DHFR inhibition is still unclear, downregulation of proteins by SM1235 in HCT116 cells indicate that benzoprims inhibit proteins downstream of RAS.

Through preclinical and early (ongoing) clinical trial data, our institution has shown the benefits of combining targeted synthetic long peptide vaccines with ICB and adjuvant stimulants in treatment of solid malignancies. This is a single institution, phase I study for patients with Stage III/IV unresectable KRAS-mutated NSCLC to evaluate safety of the pooled mutant-KRAS peptide vaccine with poly-ICLC adjuvant in combination with nivolumab and ipilimumab in the first line treatment setting. The secondary objectives are to assess the impact of therapy on mutant-KRAS specific T cell responses in the peripheral blood and estimate the progression free survival (PFS) for patients treated with this combination. Correlative studies will assess the impact of predicted KRAS mutations on mutant-KRAS specific T cell responses in the peripheral blood, as well as evaluate dynamic genomic alterations of response and resistance through ctDNA analysis.

Comprehensively, PMBA represents a new class of KRAS inhibitors having a therapeutic window in the scope of a drug candidate. The findings suggest that the PMBA analogue could inhibit the growth of human CRC in vivo through downregulation of cancer-associated biomarkers as well as reactivate expression of the MGMT gene associated with increased H3K9 acetylation and H3K4 methylation with facilitated transcriptional activation, which might be important in silencing of genes associated with upregulation in the activity of KRAS.

Based on our comprehensive survey of next generation sequencing focused on KRAS aberration, we identified approximately 2.9% KRAS amplification and 26.0% KRAS SNV in patients with metastatic solid tumors. It was demonstrated that G12V, G13D were important mutations which were related to the response to ICI treatment in real-world data.