KRAS A146

These proteins are captured through the strong interaction between the biotin label and streptavidin bead and subsequently identified by mass spectrometry. Here, we developed a protocol using CRISPR-mediated gene editing to generate endogenous BioID2-tagged KrasG12D and KrasG12V isogenic murine colon epithelial cell lines to identify unique protein proximity partners by BioID.

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.

dSTORM imaging of cell line models carrying patient-derived secondary genetic alterations revealed a distinct pattern linked to each mutation respectively. In KRASG12A, we observed a reduction in BCMA density by 2-fold as compared to wild type cells (5.9 ± 0.3 vs. 10.8 ± 1.2 localization clusters/µm2, p=0005).

KRAS is a complex genetic mutation associated with heterogeneity in PD-L1 expression and co-alterations, which could serve as biomarkers for differential outcomes. STK11 co-mutation appears to be a poor prognostic biomarker in this context.

INI1-deficient poorly differentiated carcinoma of the colon is a rare, aggressive colonic malignancy showing a serrated phenotype. Routine identification and subtyping are important keeping in mind the distinct tumor phenotype, resistance to conventional chemotherapy, and dismal prognosis.

P1, N=8, Terminated, Boehringer Ingelheim | Completed --> Terminated; Sponsor decision

Taken together, our work provided a comprehensive analysis of driver and targetable alterations in SBA, which can facilitate the practice of precision oncology in this challenging disease.

P1, N=8, Completed, Boehringer Ingelheim | Terminated --> Completed

No abstract available

P1, N=15, Terminated, Boehringer Ingelheim | N=95 --> 15 | Trial completion date: Feb 2024 --> Apr 2022 | Suspended --> Terminated | Trial primary completion date: Jan 2024 --> Apr 2022; Sponsor decision

P1, N=8, Terminated, Boehringer Ingelheim | N=124 --> 8 | Trial completion date: Jul 2024 --> Apr 2022 | Suspended --> Terminated | Trial primary completion date: Oct 2023 --> Apr 2022; Sponsor decision

P1, N=95, Suspended, Boehringer Ingelheim | Recruiting --> Suspended

P1, N=124, Suspended, Boehringer Ingelheim | Recruiting --> Suspended

For the subgroup of patients who carried a KRAS mutation and were treated with bevacizumab and doublet or triplet chemotherapy (N=156), clinical outcome was evaluated and pretreatment tumor burden was quantified as liquid biopsy circulating tumor DNA (ctDNA) mutant allele fraction (MAF) and as total tumor volume (TTV) on CT imaging... Of the 156 patients with a KRAS mutated tumor, most carried a KRAS G12 mutation (N=112, 71.8%), followed by mutations in G13 (N=15, 9.6%), A146 (N=12, 7.7%), Q61 (N=9, 5.8%) and K117 (N=5, 3.2%). High plasma ctDNA levels were observed for patients carrying a KRAS A146 mutation versus those with a KRAS G12 mutation, with a median MAF of 48% versus 19%, respectively. Radiological TTV revealed this difference to be associated with a higher tumor load in patients harboring a KRAS A146 mutation (median TTV 672 cm3 (A146) versus 74 cm3 (G12), p=0.036).

P1, N=95, Recruiting, Boehringer Ingelheim | Trial completion date: Dec 2022 --> Feb 2024 | Trial primary completion date: Oct 2022 --> Jan 2024

Patients with mCRC with a KRAS A146 mutation represent a distinct molecular subgroup of patients with higher tumor burden and worse clinical outcomes, who might benefit from more intensive treatments. These results highlight the importance of testing colorectal cancer for all KRAS mutations in routine clinical care.

P1, N=124, Recruiting, Boehringer Ingelheim | Trial completion date: Sep 2023 --> Jul 2024 | Trial primary completion date: Nov 2022 --> Oct 2023

Therefore, selection for GFP-positive cells allows us to identify those with phenotypically silent Kras edits. Ultimately, this method allows us to toggle between different mutant alleles and preserve the wild-type allele while maintaining an isogenic background.

P1, N=124, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

P1, N=124, Not yet recruiting, Boehringer Ingelheim

P1, N=95, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

P1, N=95, Not yet recruiting, Boehringer Ingelheim

The clonal and subclonal mutational landscapes of RAS WT pts were analyzed using a mCRC-focused custom ctDNA sequencing panel. Randomized pts (1:1) received mFOLFOX6 plus either panitumumab or bevacizumab. The validated ultra-deep plasma sequencing panel was concordant with tissue sequencing and detected tumor heterogeneity. The PARADIGM study will report the efficacy of anti-EGFR/VEGF therapies; post-treatment collection of ctDNA is ongoing. The relationship between therapeutic effects and clonal and subclonal mutational landscapes will be examined in the future.