Pan-KRAS Inhibitors BI-2493 and BI-2865 Display Potent Antitumor Activity in Tumors with KRAS Wild-type Allele
Antonio Tedeschi1, Fiorella Schischlik1, Francesca Rocchetti1
1Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
Abstract:
KRASG12C selective inhibitors, such as sotorasib and adagrasib, have raised hopes of targeting other KRAS-mutant alleles in patients with cancer. We report that KRAS wild-type (WT)-amplified tumor models are sensitive to treatment with the small-molecule KRAS inhibitors BI-2493 and BI-2865. These pan-KRAS inhibitors directly target the "OFF" state of KRAS and result in potent antitumor activity in preclinical models of cancers driven by KRAS-mutant proteins. In this study, we used the high-throughput cellular viability Profiling Relative Inhibition Simultaneously in Mixtures assay to assess the antiproliferative activity of BI-2493 in a 900+ cancer cell line panel, expanding on our previous work. KRAS WT-amplified cancer cell lines, with a copy number >7, were identified as the most sensitive, across cell lines with any KRAS alterations, to our pan-KRAS inhibitors. Importantly, our data suggest that a KRAS "OFF" inhibitor is better suited to treat KRAS WT-amplified tumors than a KRAS "ON" inhibitor. KRAS WT amplification is common in patients with gastroesophageal cancers in which it has been shown to act as a unique cancer driver with little overlap to other actionable mutations. The pan-KRAS inhibitors BI-2493 and BI-2865 show potent antitumor activity in vitro and in vivo in KRAS WT-amplified cell lines from this and other tumor types. In conclusion, this is the first study to demonstrate that direct pharmacologic inhibition of KRAS shows antitumor activity in preclinical models of cancer with KRAS WT amplification, suggesting a novel therapeutic concept for patients with cancers bearing this KRAS alteration.
Insights
New pan-KRAS inhibitors, BI-2493 and BI-2865, show potent antitumor activity in preclinical models. KRAS wild-type (WT) amplified tumors are particularly sensitive to these "OFF" state inhibitors, offering a novel therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- KRAS mutations drive various cancers, with selective inhibitors like sotorasib targeting specific alleles.
- KRAS wild-type (WT) amplification represents a distinct oncogenic driver, particularly in gastroesophageal cancers.
- Targeting KRAS WT amplification offers a potential therapeutic avenue beyond KRAS-mutant specific inhibitors.
Purpose of the Study:
- To evaluate the efficacy of novel pan-KRAS inhibitors, BI-2493 and BI-2865, in preclinical cancer models.
- To identify specific genetic alterations that confer sensitivity to these pan-KRAS inhibitors.
- To explore the therapeutic potential of targeting KRAS WT amplification.
Main Methods:
- Utilized the Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) assay for high-throughput screening of BI-2493 across over 900 cancer cell lines.
- Assessed antiproliferative activity of pan-KRAS inhibitors in vitro and in vivo.
- Correlated drug sensitivity with KRAS gene copy number and mutational status.
Main Results:
- Pan-KRAS inhibitors BI-2493 and BI-2865 demonstrated potent antitumor activity in preclinical models.
- Cancer cell lines with KRAS wild-type (WT) amplification (copy number >7) exhibited the highest sensitivity to these inhibitors.
- These inhibitors target the inactive "OFF" state of KRAS, showing superior efficacy in KRAS WT-amplified models compared to "ON" state inhibitors.
Conclusions:
- Direct pharmacologic inhibition of KRAS is effective against KRAS WT-amplified cancers.
- KRAS WT amplification is a predictive biomarker for sensitivity to "OFF" state pan-KRAS inhibitors.
- BI-2493 and BI-2865 represent a novel therapeutic strategy for cancers harboring KRAS WT amplification.
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