Tumor microenvironment-activated ferritin nanovector enables enhanced tumor delivery of KRASG12C inhibitors and degraders

TL;DR

A new nanomedicine platform activates in the tumor environment to deliver KRASG12C inhibitors and degraders more effectively to cancer cells.

Contribution

A tumor microenvironment-activated ferritin nanovector is developed for enhanced delivery of KRASG12C inhibitors and degraders.

Findings

The nanoplatform encapsulates Adagrasib and LC-2 and achieves efficient intracellular delivery when activated by MMP-2 and MMP-9.

In KRAS-mutated cancer models, the nanoplatform showed comparable or better therapeutic outcomes than individual drugs.

The study demonstrates a proof-of-concept for TME-activated delivery of KRASG12C inhibitors and degraders.

Abstract

Mutations in RAS oncogenes (KRAS, HRAS, NRAS) are among the most common genetic alterations in human cancers. The activating KRASG12C mutation, in particular, is a key driver in a significant percentage of non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, and lung adenocarcinoma. 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. These inhibitors function by binding to a shallow pocket between the switch-I and switch-II elements, locking KRAS in its inactive GDP-bound state. However, concerns exist regarding the efficacy and the development of resistance to Sotorasib and Adagrasib through mechanisms like secondary mutations, KRAS overexpression, and KRAS downstream pathway activation. To overcome these limitations, we developed a novel, stimuli-sensitive, tumor microenvironment-activated, ferritin-derived nanomedicine platform, named The-05. This platform, previously shown to effectively enhance payload biodistribution, plasma half-life, and reduce off-target effects in various tumors, is reported here to: 1) encapsulate high amounts of the KRASG12C inhibitor Adagrasib and the PROTAC degrader LC-2; 2) to achieve efficient intracellular delivery in vitro, once activated by matrix metalloproteases MMP-2 and MMP-9. 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.

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