KRAS G12S

This breakthrough led to the development and approval of sotorasib (AMG510) and adagrasib (MRTX849), revolutionizing the treatment of KRASG12C-dependent lung cancer. Insights from successful KRASG12C targeting informed the design of molecules addressing other mutations, often in a covalent manner. These findings offer promise for innovative approaches in addressing commonly occurring KRAS mutations such as G12D, G12V, G12A, G12S, and G12R in various cancers.

In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRASMUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.

Sotorasib showed selective inhibition in vitro and in vivo with altered tumor microenvironment, including fibroblasts and macrophages. Collectively, screening for KRAS single mutations in plasma ctDNA and the use of preclinical models of PDO and PDX with genetic mutations would impact precision medicine in the context of PDAC.

We did not confirm the negative predictive value of KRAS G12 mutation in patients treated with T/T, however, OS depends on the specific G12 mutation. In contrast, patients with KRAS G13 mutation had worse survival.

ELI-002 2P is a lymph node targeted immunotherapy comprised of Amphiphile (Amph)-modified G12D, G12R, G12V, G12C, G12A, G12S and G13D mutant KRAS peptides together with an Amph-modified CpG oligonucleotide adjuvant...Subsequent patients will receive up to 10 doses of Amph-peptides 7P 700 mcg each (4.9 mg total), together with Amph-CpG-7909 (10.0 mg) administered over a five-month treatment period...An interim analysis is planned using group sequential design for control of overall alpha 0.10. Clinical trial information: NCT05726864.

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.

Recently, others and we have shown that the mechanistic Target of Rapamycin Complex 2 (mTORC2) is a Ras effector in Dictyostelium and mammalian cells...Interestingly, our results suggest that K-Ras and mTORC2 promote A549 cell migration but as part of different pathways and independently of Ras's mutational status. Moreover, further characterization of the A549 cells revealed that loss of mutant K-Ras expression for the wild-type protein leads to an increase in cell growth and proliferation, suggesting that the A549 cells have low KRAS mutant dependency and that recovering expression of wild-type K-Ras protein increases these cells tumorigenic potential.

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.

We developed a comprehensive multiplex mutant detection method with high sensitivity and specificity. This study demonstrates the strong potential of Absolute Q dPCR as a powerful multiplex platform for early mutation detection and monitoring in liquid biopsy samples.

These findings imply the genetic basis of KRAS with immunotherapeutic target molecules based on a real-time platform. This study also suggests the highly heterogeneous nature of cancer cells, which may facilitate the assessment of clonal dynamics across a single patient's disease.

"Recently, sotorasib was developed as a molecular targeted drug for KRAS mutations...By the PNA-LNA PCR clamp method, G12C mutation of surgical specimens was detected successfully. The PNA-LNA PCR clamp method is expected to be applied to the detection of druggable G12C mutations."

The circumvention of gefitinib resistance by flunarizine was further demonstrated in an EGFR TKI (erlotinib)-refractory patient-derived tumor xenograft (PDX) model in vivo. Importantly, flunarizine was also shown to significantly potentiate the tumor growth suppressive effect of gefitinib in EGFR TKI-refractory PDX in vivo. The findings advocate for the translational application of flunarizine to circumvent gefitinib resistance in the clinic.

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.

Re-challenge therapy with a combination of anti-EGFR, anti-VEGF, and FOLFIRI chemotherapy was found to be ineffective in a patient with 0.38% KRAS G12D mutation in baseline ctDNA. Our study suggests that the detection of low-frequency KRAS mutations in ctDNA could be used as a predictor of treatment response in mCRC patients.

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.

Multifactorial analysis showed that TP53 mutation (HR 2.198, 95% CI 1.006-4.803; P = 0.048) and RB1 mutation (HR 8.798, 95% CI 1.604-48.269; P = 0.012) were independent risk factors for PFS with first-line targeted therapy. Conclusions This research added to the evidence that co-alterations such as TP53, MET, and RB1 are prospective prognostic biomarkers in NSCLC patients treated with EGFR-TKI.

Conclusions In the largest analysis of the association of KRAS exon 2 and BRAFV600E mutations and disease outcome in resected stage III CC, either mutation was associated with significantly shorter DFS, OS and SAR in MSS tumors, but only with shorter SAR in MSI-H tumors. In addition, all KRAS codon 12 and 13 mutations had similar prognostic value.

This research added to the evidence that co-alterations such as TP53, MET, and RB1 are prospective prognostic biomarkers in NSCLC patients treated with EGFR-TKI.

The clinicopathological characteristics of included patients were consistent with the published literature. In the majority of KRAS-mutated patients included in this study, the use of NGS allowed for the detection of additional genetic alterations with potential clinical significance.

Another HDACi panobinostat also showed potential anticancer effect in both H358 and A549 cells via Nrf2 pathway. In summary, belinostat is effective in killing KRAS-mutant human lung cancer cells by regulating mitochondrial metabolism which could be used as biomarkers for preclinical and clinical studies.

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.

These findings confirm that KRAS mutation location may predict survival outcomes in patients with mCRC, and suggest that pre-/post-operative bevacizumab plus metastasectomy provides survival benefits in patients with KRAS mutations.

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."

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.

For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible, safe, and offered clinical benefit, supporting the prospective evaluation of this combination.

Furthermore, we observed a synergic effect on cytotoxicity and apoptosis induction, as well as a notable inhibition of the MAPK and AKT-mTOR pathways after treatment with the combination, predominantly in KRAS-mutated cells (H23 and A549). The combination of metformin with sotorasib synergistically enhanced cytotoxicity and apoptosis induction in lung cancer cells, regardless of KRAS mutational status.

The combination of metformin with sotorasib showed synergic effects on cytotoxicity, increased apoptosis induction, and a remarkable inhibition of downstream proteins involved in the signaling of growth factor receptors in all tested cells. Moreover, these results suggest a sensitizing effect of metformin to sotorasib treatment in cells without KRAS mutations, such as H522.

To this end, unlike the control HDACI vorinostat, flunarizine (tested at the resistance circumventing concentrations) did not appreciably affect acetylation of representative non-histone proteins (including α-tubulin and p53) relevant to drug resistance. The findings advocate further clinical evaluation of the repurposing use of flunarizine to overcome gefitinib resistance.

Current analyses revealed that a significant proportion of CRC patients in the East Coast of Peninsular Malaysia have KRAS mutations, where this frequency is higher compared to those in the West Coast. The findings of this study would serve as a precursor for further research that explores KRAS mutational status and the profiling of other candidate genes among Malaysian CRC patients.

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

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

In contrast, ERK phosphorylation was not suppressed by concurrent milademetan and KIF5B::RET inhibition using selpercatinib (in ECLC5-GLx), MET inhibition using capmatinib (in LUAD12c), or KRASG12C inhibition using sotorasib (in SW1573)...In vivo, milademetan+trametinib was more effective than milademetan or trametinib alone in ECLC5-GLx (p<0.0001 and p<0.0001, respectively), LX-285 (EGFRex19del/MDM2amp) (p<0.0001 and p<0.0001, respectively), L-13BS1 (model resistant to capmatinib) (METex14/MDM2amp) (p<0.05 and p<0.0001, respectively)...CONCLUSION Combined MDM2/MEK inhibition is effective in patient-derived LUAD models harboring MDM2amp. This combination, potentially applicable to LUADs with a wide variety of oncogenic driver mutations and kinase fusions will be investigated as part of a phase 1/2 clinical trial.