Collectively, our findings suggest that the combination of DT2216/everolimus potentiates the anti-tumor efficacy of MRTX1133 associated with enhanced apoptosis induction and inhibition of compensatory survival signaling.

P1, N=17, Terminated, AstraZeneca | Phase classification: P1/2 --> P1

Two covalent inhibitors, sotorasib and adagrasib, which target a specific codon 12 mutation (G12C), had received accelerated approvals for clinical use. This appears to be due to a lack of effect on downstream KRAS effectors such as the ribosomal protein S6, highlighting the need for strategies that take into account potential context-dependent processes. Together with other recent reports on high-affinity binding of MRTX1133 to other non-G12D KRAS mutants, our findings further reveal the usefulness of MRTX1133 as a chemical probe that continues to provide novel insights on KRAS biology and inhibition mechanisms.

While KRAS was long considered undruggable, the development of mutant-specific inhibitors, including covalent inhibitors targeting KRASG12C (such as Sotorasib and Adagrasib) and non-covalent inhibitors targeting KRASG12D (such as Mirati's MRTX1133), has shown promise. In cellular models of KRAS-mutated NSCLC and PDAC, this nanoplatform achieved comparable or superior therapeutic outcomes with respect to the individual drugs. This study provides a compelling proof-of-concept for the in vitro delivery of KRASG12C mutant-specific inhibitors and degraders to human tumors through a tumor microenvironment-activated nanomedicine approach and lays the groundwork for future studies in physiologically relevant models to assess TME-specific activation and tumor selectivity.

Notably, combining a G9a degrader (G9D-4) with the KRASG12D inhibitor MRTX1133 elicited synergistic anti-tumor effects in KRASG12D-mutant tumoroids. Overall, our study provides preclinical insights from a small PDAC and BTC tumoroid cohort, supporting tumoroid-based platforms for exploratory drug screening and pharmacogenomic analyses and suggesting potential therapeutic directions that warrant further validation.

P1/2, N=401, Recruiting, Abbisko Therapeutics Co, Ltd | Not yet recruiting --> Recruiting

P1, N=108, Recruiting, AstraZeneca | N=24 --> 108

P1/2, N=17, Terminated, AstraZeneca | Trial completion date: Jun 2026 --> Jan 2026 | Active, not recruiting --> Terminated; The decision to cease enrolment and proceed with the early termination of the ALAFOSS 01 (D7080C00001) study was based on strategic company portfolio prioritization.

P2, N=30, Recruiting, The First Affiliated Hospital with Nanjing Medical University

Combined MRTX1133 and olaparib treatment produced synergistic cytotoxicity in vitro and durable tumor regression in vivo, even in MRTX1133-resistant models, and remodeled the tumor immune microenvironment with enhanced CD8+ T-cell infiltration. These findings demonstrate that co-targeting KRASG12D and PARP exploits an induced DNA-repair vulnerability to achieve synthetic lethality and immune activation in KRASG12D-driven PDAC.

These findings establish a combination strategy that overcomes a significant mechanism of resistance to MRTX1133 and offer a potential treatment option for pancreatic cancers, including those refractory to current therapies.