NRAS G12C

KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical efficacy in KRASG12C tumors. Structural and reciprocal mutagenesis studies suggested that differences in isoform-specific binding are mediated by a single amino acid: Histidine-95 in KRAS (Leucine-95 in NRAS). A patient with NRASG12C colorectal cancer treated with sotorasib and the anti-EGFR antibody panitumumab achieved a marked tumor response, demonstrating that sotorasib can be clinically effective in NRASG12C-mutated tumors.

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

RAS mutations also decrease efficacy of the BCL2 inhibitor venetoclax now widely used in AML, suggesting an anti-apoptotic influence of MAPK signaling...Using GSEA we found that gilteritinib stimulated adaptive interferon/inflammatory gene signatures at 16h drug treatment, but this response was restrained by addition of SEL120...We speculate this latter effect may in part alter an AML cell's differentiation state to sensitize cells to apoptosis, though further study to explore this hypothesis is needed. Our in vitro and in vivo efficacy data further validated combined FLT3i/CDK8i as a promising investigational strategy to pre-empt or overcome MAPK-mediated FLT3 TKI resistance.

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.

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

The patient was given folforinox + avastin during 3 months, then Avastin+Xeloda as maintenance treatment. The question is: "Are RAS and BRAF mutations really exclusive to each other"? It seems difficult to answer: even if it's a rare event, it is important to search for BRAF mutations even if RAS is mutatedin specific patients.

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

It mainly occurs in the sigmoid colon and rectum. It typically has aggressive clinical courses, dismal prognosis and characteristic histological features and immunophenotype, which highlight the importance of recognizing this entity for clinicians and pathologists.

It is feasible to perform NGS analysis using reference laboratories. There is population of patients, willing to undergo specialized tests. Actionable molecular data information can be collected and utilized for patient care.

However, we also found mutations that are specific for one sister cell line only, pointing to individual subclones of the primary tumor as originating cells. Our data show that sequential sister cell lines can be used to study the clonal development of tumors and to elucidate the function of common and clone-specific mutations.

We sought to investigate mechanisms of acquired resistance to FGFRi and approaches to overcome resistance. Longitudinal plasma samples were collected from patients with FGFR pathway alterations enrolled in the futibatinib phase I trial (NCT02052778) and sequenced using a targeted, 73-gene panel... Convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi therapy. Work is ongoing to determine if targeting co-alterations may enhance the efficacy of FGFRi in FGFR2-fusion driven malignancies.

Collectively, our data suggest that SHP2 inhibition increases the apoptotic dependency on BCL2 through up-regulation of the pro-apoptotic BMF, a mechanistic rationale to synergistically inhibit both targets. We provide preclinical evidence that co-targeting SHP2 and BCL2 is a potential effective therapeutic strategy in RTK-driven AML.

In the mouse syngeneic Lewis Lung Carcinoma (LL/2) cell line, which carries both KRAS p.G12C and NRAS p.Q61H mutations, intrinsic resistance to KRASG12C inhibition was observed, but combination treatment with the MEK inhibitor trametinib demonstrated synergistic improvement in the effects on viability. Taken together, these data demonstrate that His95-binders like sotorasib display superior potency and off-target selectivity, as well as unique activity against all versions of RASG12C. In addition, characterization of potential resistance mechanisms to sotorasib will inform combination strategies in the clinic.