Dual inhibition of GTP-bound (ON) and GDP-bound (OFF) KRAS^G12C suppresses PI3Kα and leads to potent tumor inhibition

Background

Around 30% of all human cancers are driven by oncogenic RAS mutations. For decades, RAS was considered undruggable, but the recent development of selective KRASG12C inhibitors has represented a major breakthrough in the field. These first-generation agents (such as sotorasib and adagrasib) covalently bind to the mutant cysteine in the inactive (GDP-bound) KRAS protein, and are therefore known as KRASG12C (OFF) inhibitors. These drugs were rapidly approved for the treatment of KRASG12C-mutant non-small cell lung cancer (NSCLC). However, their clinical success has been limited, mainly due to rapid adaptive reactivation of RAS-MAPK signaling, resulting in drug resistance.
KRAS (ON) inhibitors targeting the active (GTP-bound) KRAS protein are a novel approach that could overcome some of the adaptive mechanisms that promote resistance to (OFF) inhibitors. However, studies shedding light on the specific mechanisms that differentiate their activity are lacking.
In this preprint, Parker and colleagues assess the activity of BBO-8520, a novel dual inhibitor of both GTP-bound and GDP-bound KRASG12C, in NSCLC models in vitro and in vivo.

Key findings

1. BBO-8520 shows potent antitumoral activity in KRASG12C NSCLC cells, superior to sotorasib.
Dual KRASG12C (ON/OFF) inhibition mediated by BBO-8520 strongly impaired cell viability and proliferation, and reduced RAS-GTP and phospho-ERK levels in a broad panel of KRASG12C-mutant NSCLC cell lines. These antitumoral effects were achieved at 10-100-fold lower drug concentrations compared to sotorasib, demonstrating superior activity and greater suppression of cell proliferation over longer time frames.

Figure: Only BBO-8520 achieved a long-term suppression of cell proliferation in the KRASG12C-mutant NSCLC cell line H2122. Reproduced from Figure 2A of the preprint.

2. BBO-8520 achieves a more durable response due to improved inhibition of PI3K-AKT signaling.
Feedback reactivation of MAPK signaling, mediated by wild-type HRAS and NRAS, occurred after prolonged treatment with both BBO-8520 and sotorasib. However,
phospho-AKT levels were consistently lower in BBO-8520-treated cells, leading to a more durable suppression of proliferation.
To confirm this mechanism, the authors combined sotorasib with a tool compound that prevents RAS-mediated PI3Kα activation. Indeed, this dual treatment reduced phospho-AKT levels and impaired cell proliferation to the same level as BBO-8520 treatment.

3. BBO-8520 exhibits potent in vivo activity which is phenocopied by a combination of sotorasib and a RAS-PI3Kα breaker.
BBO-8520 induced tumor regression and showed greater efficacy than sotorasib in different murine xenograft models. Similar to the in vitro results, the combination of sotorasib with BBO-10203 (a clinical RAS-PI3Kα breaker) achieved equivalent efficacy to BBO-8520 monotherapy. Conversely, the addition of BBO-10203 did not improve the efficacy of BBO-8520 in most models.

What I like about this preprint

The work by Parker and colleagues convincingly demonstrates the preclinical efficacy of this novel dual KRASG12C (ON/OFF) inhibitor, and thoroughly compares its activity with a first-generation KRASG12C (OFF) inhibitor. The results have clear translational relevance, since BBO-8520 exhibits increased potency and a more durable response than sotorasib, a drug that is already approved for clinical use in NSCLC. Furthermore, the authors provide relevant mechanistic explanations of the results, opening new avenues for the combination of RAS-MAPK and PI3K-AKT inhibition in NSCLC.

Questions for the authors

1. Have you checked phospho-AKT levels in tumor samples to further confirm this mechanism in vivo?
2. What are the benefits of using a dual KRAS (ON/OFF) inhibitor, in comparison with a combination of one (ON) inhibitor and one (OFF) inhibitor?
3. Your work demonstrates the advantages of KRAS (ON) inhibition over (OFF) inhibition in KRASG12C-mutant NSCLC. You also acknowledge the importance of WT RAS in the adaptive feedback reactivation of MAPK signaling. Therefore, I believe that the use of a pan-RAS (ON) inhibitor would be a logical option. Can you discuss this?

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