KRAS G12R

Together, this study demonstrated that KRASG12R is capable of driving tumorigenesis despite the reduced ERK/MAPK nuclear translocation and transcriptional output. Although human KRASG12D and KRASG12R-mutant tumors display unexpected similarities in PI3K activity, the differential ERK/MAPK signaling activity and the extrinsic consequences on the TME provide support for using KRASG12R mutation status as a prognostic biomarker for therapeutic strategies.

This report demonstrates that fully automated cfDNA-based NGS can achieve clinically meaningful genomic profiling within 27 h in a community hospital. This advancement addresses the time and cost barriers of traditional NGS analysis and represents a significant step toward promoting precision medicine in community healthcare.

Further, EGFR inhibitor erlotinib synergized with the RAS(ON) multi-selective inhibitor RMC-7977 in KRASQ61H-mutant PDAC cell lines and in cell lines with highly active EGFR by mitigating ERK rebound activity. KRASi-resistant cell lines featured sustained ERK/MAPK dependence despite decreased ERK activity. Together, these findings enhance the understanding of intrinsic and acquired resistance to KRASi and identify therapeutic vulnerabilities that can potentially be exploited for KRASi combination therapies in pancreatic cancer patients.

KRAS mutation analysis of both pancreatic tumor and lung tumor is useful for distinguishing solitary pulmonary nodules in postoperative pancreatic cancer patients. KRAS mutation analysis identified PLC more frequently than conventional pathological diagnosis.

Degrader activity profiling in relevant cancer cells supported the discovery of ACBI4, a PROTAC which forms a highly stable and cooperative ternary complex between VHL and GTP-bound KRAS and which potently degrades KRASG12R, leading to antiproliferative effect in KRAS mutant-driven cancer cells. ACBI4 provides a new chemical tool for studying the impact of degrading KRAS(on) mutants, which is not possible with current pan-KRAS inhibitors or degraders.

To substantiate the preclinical findings, the utility of MEKi in combination with the autophagy inhibitor hydroxychloroquine was analyzed in patients with KRASG12R mutated metastatic PDAC...Three patients had impressive disease control: two had stable disease of 11 and 22.7 months, and one achieved a partial response with an 83% decrease in tumor size that lasted for 8.9 months. Overall, this work highlights how systems-based approaches in precision medicine can uncover mechanistic insights to guide the identification of PDAC patients most likely to benefit from tailored therapeutic strategies.

Thus, this study uncovered a mechanism that supports elevated PI3K signaling in PDAC, thereby reducing the need for KRAS to directly activate the PI3K pathway. PTEN inactivation by intramolecular disulfide bond formation and elevated expression of PI3K isoforms in pancreatic cancer leads to unchecked KRAS-independent PI3K signaling, highlighting the need for therapeutic approaches targeting constitutive PI3K signaling.

GSEA and TIDE revealed that they were correlated with Cluster of Differentiation 4 Positive T Cell (CD4+ T cell) activation in opposite directions. SERPINA3 overexpression and KRAS G12R were together identified as novel gene signatures to predict poor PFS of PDAC patients receiving gemcitabine-based treatment.

Selective RET inhibitors such as pralsetinib have become the standard of care for patients with RET fusion-positive non-small cell lung cancer (NSCLC)...These findings suggest that ctDNA-based surveillance using multiple metrics, enables early forecasting of tumor response and progression in RET fusion-positive NSCLC. Early ctDNA clearance and dynamic profiles provide non-invasive biomarkers for early intervention, warranting further validation with ctDNA-guided strategies.

Defining how KRAS mutants drive distinct outcomes in human pancreatic cancer is critical for developing allele-specific therapeutic approaches. This study unveils a hierarchy among KRAS G12D , KRAS G12V , and KRAS G12R to drive tumor initiation, owing to heterogeneous activation of EGFR, PI3K/AKT, and RAC1 signaling, thus revealing mutation-specific evolutionary paths in pancreatic tumorigenesis.

P=N/A, N=80, Recruiting, Mandana Kamgar, MD | N=40 --> 80 | Trial completion date: Feb 2025 --> Aug 2027 | Trial primary completion date: Feb 2025 --> Aug 2027

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