KRAS Q61

The Agena iPlex HS Lung Panel on the MassARRAY System is highly tolerant of poor quantity and quality DNA, recovering and delivering accurate results on samples that would otherwise fail NGS-based analysis.

The recent approval of KRASG12C inhibitors, adagrasib and sotorasib, has validated KRAS as a direct therapeutic target and demonstrated the feasibility of selectively targeting specific RAS mutants. Despite these challenges, new approaches have generated optimism about targeting specific RAS mutations in an allele-dependent manner for cancer therapy, supporting by compelling biochemical and structural evidence, which inspires further exploration of RAS allele-specific vulnerabilities. This review will discuss recent advances and challenges in the development of therapies targeting RAS signaling, highlight emerging therapeutic strategies, and emphasize the importance of allele-specific approaches for leukemia treatment.

KRAS Q61 and NRAS Q61 mutations are promising predictors for OS in CRLM patients after hepatectomy. Postoperative chemotherapy may significantly benefit CRLM patients with RAS mutations, particularly those identified as high-risk.

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.

P2, N=34, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025

Detection of KRAS mutation in liquid biopsies of patients with metastatic PDAC is associated with worse OS. KRAS G12D/Q61 alterations detection is associated with worse OS compared to other KRAS mutation subtypes. Ct-DNA detection of co-occurring CDKN2A mutation is associated with worse OS in patients with KRAS positive metastatic disease.

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

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.

MDC-MMAE was pre-clinically evaluated both in-vitro and in-vivo, in human MM cell lines, patient cells and a doxycycline inducible mutant KRAS cell system...It can also be combined with other MM standard of care drugs and with immunotherapy drugs to have a potentially important clinical effect. In collaboration with Tezcat Biosciences, the MDC-MMAE technology has achieved a phase II SBIR for advancement to clinical application.

The MAPK DM, high TMB and persistent genomic instability suggest roles for MAPK-targeted therapies, immunotherapies and DNA damage repair pathway inhibitors, respectively, in EMD. Recurrent codon 61 mutations in RAS suggest a specific role in EMD progression.

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.

P1, N=16, Terminated, National Cancer Institute (NCI) | Active, not recruiting --> Terminated; Inadequate accrual rate

KRAS mt subtypes may confer different PDAC phenotypes. In our cohort, G12R is associated with improved OS while G12V correlates with worse prognosis in de novo metastatic disease. Additionally, there are differences in genomic variations and RNA expression between the KRAS mt subtypes.

Te dynamic change of ctDNA during systemic treatment allows the prediction of treatment response and is associated with OS and PFS. Progressive disease was correctly predicted in 100% of patients with preemptive detectable ctDNA after 2 weeks (ctDNA) compared to 12 weeks with current gold standard (CT), enabling change of treatment >80% earlier hereafter.

These mutations were once considered “undruggable” for many years until appearance of sotorasib...Its inhibitory effects on tumor growth were more remarkable in the combination of anti-PD1 antibodies. Moreover, the vaccine could elicit specific T and B cell responses, which are crucial in anti-cancer immunotherapy.

MAPK DM were frequent in EMD, and detectable in ctDNA, suggesting roles for both MAPK-targeted therapies and for ctDNA as a biomarker in these patients. A high TMB was identified in patients lacking a MAPK driver mutation; immunotherapy should be considered in this subgroup.

P2, N=34, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2023 --> Jan 2024

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.

Patients undergoing surgery had a reduced percentage of tumors with KRAS-G12D. When determining the prognosis of individuals with radically resected PDAC, reference markers for KRAS mutation subtypes can be employed.

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

Our study demonstrated the clinical relevance of minor mutant subclones in EGFR signaling pathway genes in plasma for predicting response to anti-EGFR treatment. Although sample size of this study was small, preferable threshold for distinguishing responders from non-responders may be 0.5% as VAF of these gene mutations. Clinical trial information: 000034923.

Complex and miscellaneous karyotypes showed KRAS mutations more often. KRASK117N mutations were consistently associated with TET2 and ASXL1 mutations and mutually exclusive with NPM1 and DNMT3A.

P1, N=45, Recruiting, UNC Lineberger Comprehensive Cancer Center | Active, not recruiting --> Recruiting

P1, N=45, Active, not recruiting, UNC Lineberger Comprehensive Cancer Center | Trial completion date: Oct 2023 --> Apr 2026 | Trial primary completion date: Oct 2022 --> Jul 2024

The change in magnitude of ctDNA during systemic treatment allows the prediction of treatment response and is associated with both OS and PFS. This finding adds significant clinical potential to the already established prognostic value of ctDNA positivity in metastatic pancreatic cancer.

KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cell lines exhibited KRAS-dependent growth and, as observed with KRAS-mutant PDAC, were susceptible to concurrent inhibition of ERK-MAPK signaling and of autophagy. Our results uncover phenotypic heterogeneity among KRAS mutants and support the potential utility of therapeutic strategies that target KRAS mutant-specific signaling and cellular output.

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.

In addition, HRAS Q61 was found to be correlated with worse prognosis in pts treated with pembro (HR = 2.779, 95% CI [1.04-7.423], p =0.03) but not G12 or G13, and displayed the highest MPAS score (p = 0.05), which had previously been demonstrated to indicate immune evasion...HRAS mt SCC also showed an immune-cold TME associated with high MAPK pathway activation and high LAG3 expression. This warrants further investigation, in particular in HRAS Q61 or HRAS mt SCC, with combination therapies targeting MAPK pathway or LAG3 protein.

The associations we found and the mutational AF we reported may help to understand disease processes and may be considered as potential CCR biomarker candidates. In addition, we propose representative mutation panels associated with specific clinical and histopathological features of CRC, as a unique opportunity to refine the degree of personalization of CRC treatment.

The TME of KRAS mt PDAC shows IC patterns similar to KRAS mt CRC. Actionable IO-targets, such as PDL1, are enriched in tumors harboring specific variants of KRAS mt PDAC including the targetable G12C variant. If G12D becomes druggable, it could be targetable in 35% patients with PDAC or 15% in CRC.

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

The genomic landscape of HRASm are significantly different from that of NRASm, implying their distinct roles in tumorigenesis. HRASm also demonstrated higher MAPK activation, suggesting that they could potentially benefit from agents targeting on this pathway. In addition, HRASm displayed more immunogenic features, associated with down-regulation of angiogenesis pathway, revealing a potential higher susceptibility of HRASm to immunotherapy.

HRAS has been indirectly targeted with tipifarnib, a farnesyltransferase inhibitor rendering HRAS inactive in head and neck tumors... HRAS mutations are detectable but uncommon events in NSCLC and significantly enriched in squamous histology. HRAS mutations often occur with PIK3CA co-mutations and trended towards higher activation of MAPK pathway and MSI-H frequency. This warrants further investigation on possible clinical applications of HRAS pathway inhibitors and utility of immune checkpoint inhibitors for this subset of NSCLC.