"Targeting KRAS for Overcoming Chemoresistance in PDAC"

In a groundbreaking study published in Nature Cancer, Huang et al. have discovered a new approach to target KRAS-driven cancers, such as pancreatic ductal adenocarcinoma (PDAC), by promoting KRAS degradation through a previously unrecognized endogenous regulator, ADAM9 (A Disintegrin And Metalloproteinase domain 9) [4]. This novel mechanism of KRAS degradation could potentially offer significant benefits over direct pan-RAS inhibitors that often suffer from off-target effects and may circumvent resistance to mutant-specific inhibitors.

PDAC is one of the most lethal malignancies, primarily driven by oncogenic mutations in the KRAS gene. Recent advances have enabled the development of strategies to target KRAS (directly or indirectly) in PDAC and other KRAS-driven cancers. However, concerns regarding resistance against mutant-specific drugs remain, particularly in response to monotherapy.

Huang et al. demonstrate that ADAM9 indirectly promotes KRAS stability through transcriptional repression of the plasminogen activator inhibitor 1 (PAI-1), which binds to KRAS and the autophagosomal adapter protein LC3 to induce lysosomal KRAS degradation. PAI-1 functions as a selective autophagy receptor and also binds to other RAS isoforms independently of their mutational status, indicating a potential means for universal RAS inhibition [4].

The authors conducted an in silico small-molecule screen and identified a selective small-molecule ADAM9 inhibitor that promotes KRAS degradation by increasing PAI-1 levels and induces antitumor activity in multiple in vitro and in vivo PDAC model systems. Notably, ADAM9 inhibition enhanced sensitivity to the first-line agent gemcitabine and mitigated gemcitabine-induced chemoresistance [4].

This discovery comes at a critical time, as current FDA-approved selective KRAS inhibitors, such as sotorasib and adagrasib, specifically target the KRAS(G12C) variant but are of limited relevance for patients with PDAC, as only approximately 1% of these cancers harbor the KRASG12C mutation. For the mutant versions more commonly found in PDAC, KRAS(G12D) and KRAS(G12V), several specific inhibitors are being assessed in clinical trials and others are still in preclinical development.

The study by Huang et al. suggests that targeting the process regulating KRAS protein stability through selective degradation, as demonstrated by their research, could offer critical benefits over direct pan-RAS inhibitors. This approach may also circumvent resistance to mutant-specific inhibitors, caused by reactivation of the RAS pathway through either the acquisition of additional mutations, intratumoral KRAS mutation heterogeneity, or the compensatory activation of wild-type KRAS alleles.

The findings by Huang et al. contribute to the expanding field of RAS-targeting strategies, which include proteolysis-targeting chimeras (PROTACs), ubiquitination-independent degradation using the chemical knockdown with affinity and degradation dynamics (CANDDY) technology, and chimeric toxins targeting RAS. These diverse molecular attributes and cellular processes highlight the potential of indirect KRAS targeting in addressing unresolved issues, such as rapid resistance to allele-specific inhibitors, unfavorable bioavailability of current RAS degraders, and improved selectivity.

Source:

Laura Leonhardt & Matthias Hebrok. KRAS degradation averts PDAC chemoresistance. Nat Cancer 5, 375–377 (2024). <https://doi.org/10.1038/s43018-023-00708-7>