MRTX1133

Likewise, a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment...Of importance, this combination therapy was well tolerated. In sum, these results should guide the development of new clinical trials that may benefit PDAC patients.

It demonstrates that targeting these lesions can yield outcomes that meet or exceed the benchmarks set by the NAPOLI-1 trial (liposomal irinotecan plus 5-fluorouracil and leucovorin), with a median overall survival of 6.2 months and progression-free survival of 3.1 months. Objective response rates reach 33% with adagrasib in KRAS G12C PDAC, 22% with olaparib maintenance in germline BRCA1/2 cancers, and over 50% with RET or NTRK inhibitors with fusion alterations; pembrolizumab produces durable benefit in the 1-3% of tumours that are MSI-H/dMMR. Emerging data highlight NRG1 fusions (overall response rate 42% with zenocutuzumab), HER2 amplification, MTAP deletion with PRMT5 dependency and variant-specific (MRTX1133) or pan-RAS (daraxonrasib) inhibitors as the next frontier...Taken together, these advances represent a substantive therapeutic progress in PDAC over the past decades, even though they currently apply to a minority of patients. These findings underscore the necessity of comprehensive next-generation sequencing for every patient with advanced disease, enabling identification of rare, yet clinically meaningful, targets and moving PDAC management towards a precision-oncology paradigm.

We evaluated this nanocarrier-based therapeutic strategy for delivering the KRASG12D inhibitor MRTX1133 in KRASG12D-mutant cell lines and animal models...Mechanistically, it reprograms the tumor microenvironment by sustaining MAPK and PI3K pathway inhibition, reducing EGFR phosphorylation, enhancing CD8+ T-cell infiltration, and restoring antitumor immunity through PD-L1 blockade. By exploiting the signaling vulnerabilities of KRAS-driven tumors, our hybrid nanovesicle platform provides a promising therapeutic strategy for overcoming resistance and improving therapeutic response in KRAS-mutant NSCLC.

Our findings reveal that the efficacy of the clinical-stage KRASG12D inhibitor MRTX1133 varies, with notable resistance being observed in some cell line and organoid models...The rationale for targeting HSP90, which is preferentially activated in cancer cells, alongside KRASG12D, arises from the ability of HSP90 inhibition to destabilize substrate client proteins that are essential for cancer cell survival and have also been implicated in resistance to KRAS inhibitors. This dual inhibitor approach presents a promising new strategy to combat de novo and acquired drug resistance in KRASG12D-mutated cancers and potentially paves the way for improved clinical outcomes by addressing the complex molecular mechanisms underlying cancer cell evolution that enables resistance to conventional inhibitors.

These findings demonstrate that M1C confers resistance of PDAC to KRAS G12D inhibition and identify M1C as a potential target for ADC treatment of PDAC patients who are refractory to KRAS inhibitors.

Subsequently, we incorporated the warhead onto MRTX-1133, a potent ligand of the KRAS (G12D) mutant, to generate a novel TCI called KN2-H...It also possessed strong antiproliferative activity against KRAS (G12D) mutant cell lines by downregulating RAS oncogenic signaling. Our findings provide a novel strategy for designing novel TCIs targeting carboxyl residues, based on acyl diazo warheads.

These findings establish VEGFA-VEGFR2 signaling by PI3Kγ activation as a key driver of acquired resistance to KRAS G12D inhibition and provide a rationale for combining VEGFA-VEGFR2 inhibition with KRAS blockade in KRAS-mutant cancers. VEGFA-VEGFR2 signaling activation is a common feature of MRTX1133 resistance in KRAS G12D cancer cells Nuclear translocation of SP1 by AKT activation promotes VEGFA transcription in MRTX1133-resistant modelsInteraction of p110γ-p101 with KRAS activates PI3Kγ in the resistant models VEGFA-VEGFR2 inhibition reverses MRTX1133 resistance in vitro and in vivo.

Pancreatic cancer driven by the KRASG12D mutation faces therapeutic challenges from KRAS undruggability and acquired resistance to inhibitors like MRTX1133 via secondary mutations (e.g., Q95/Y96)...In vivo, ZJK-807 (30 mg/kg, subcutaneous) achieved 47% tumor growth inhibition in AsPC-1 xenografts with favorable pharmacokinetics. This study presents a CRBN-based PROTAC to selectively target and degrade resistant KRASG12D mutants, establishing a groundbreaking approach for KRAS-driven malignancies.

These findings may provide guidance for development of clinical trial combination regimens including cirtuvivint, CC-671 or iadademstat. Full data sets are available on PubChem.

Recently, small molecule inhibitors like MRTX1133, which target KRAS G12D, have shown efficacy in inhibiting PC growth...The loss-of-function mutation in mbk-1 (DYRK1A homologous gene) could inhibit the multivulva (Muv) phenotype in nematodes with KRAS G12D. Collectively, our findings indicate that HM could suppress the RAS/MAPK pathway by inhibiting DYRK1A kinase activity, suggesting that DYRK1A could serve as a therapeutic target for PC treatment.

Treating the spheroids with MRTX1133 revealed enhanced drug response profiles compared to 2D cultures. This study underscores the critical importance of 3D multicellular model in preclinical drug screening and their potential to bridge the gap between in vitro studies and clinical outcomes.

Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations...RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC.