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Overcoming EGFRi Resistance Through Transomic Analyses

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Pepper Bio is on a mission to put an end to untreatable diseases by enabling more effective drug discovery through the use of transomic analysis. We do this using our COMPASS platform that integrates data across the genomic, transcriptomic, proteomic, and phosphoproteomic biological layers to uncover global, functional and causal understanding of complex biological processes.

At the 2023 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference, hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC), we are presenting research showcasing our platform’s ability to circumvent drug resistance in NSCLC by finding new targets that avoid the challenges associated with targeting epidermal growth factor receptors (EGFR) directly.

In oncology, often one of the toughest challenges is finding effective treatments for patients who have developed resistance to existing drugs. In fact, 90% of cancer deaths can be attributed to multi-drug resistance in patients receiving traditional chemotherapeutics or novel targeted drugs. Lung cancer, particularly non-small cell lung cancer (NSCLC), underscores this challenge. 

Our research set out to dig into this issue. Using transomics, we identified and validated non-EGFR targets to destroy tumors resistant to osimertinib, a 3rd gen EGFR inhibitor (EGFRi) and the current standard of care for EGFR mutant (EGFRm) NSCLC.

Research Overview

Some of our previous research demonstrated that our platform can differentiate between approved and failed EGFRi that have been designed to treat EGFRm NSCLC. Through that work, we identified that the transomic signature for osimertinib was significantly different from comparator drugs that failed during late-stage clinical trials. 

In this project, we went beyond differentiating existing EGFRi to focus on identifying targets that can mimic the pharmacological effects of EGFRi in EGFRm while avoiding the resistance challenges associated with EGFR directly. To identify non-EGFR targets to treat osimertinib-resistant NSCLC we collected data from two sources: (i) osimertinib-treated EGFRm cells to identify targets that could mimic its effects, and (ii) human EGFRm NSCLC tumor vs. normal-adjacent tumor (NAT).  

Our proprietary target prioritization algorithm integrated the transomic data with prior knowledge datasets to rank targets, which were then filtered to select targets with pharmacological tool compounds (PTCs).  The PTCs were used to evaluate the targets in a xenograft model of osimertinib resistant NSCLC, PC9-Del19/T790M/C797S; which contains the activating EGFR mutation (ex19del), and two mutations conferring EGFRi resistance, T790M gatekeeper mutation, and C797S which confers resistance to osimertinib.


Among the tested targets, 82% (14 out of 17) exhibited over 30% inhibition of tumor growth. Furthermore, 53% (9 out of 17) of these targets demonstrated over 50% inhibition by PTCs. One drug compound even yielded over 85% inhibition, effectively halting tumor growth. 

These results underscore the potential of COMPASS’s transomic analysis in identifying novel drug targets for difficult-to-treat cancers such as osimertinib-resistant NSCLC.

This research is just one validating step on our journey to transform the drug development process and put an end to untreatable diseases. Ongoing validation studies are currently underway to identify novel clinical targets and drug candidates for other complex cancers, and we look forward to presenting research on these studies in the coming months. 

If you’d like to learn more about this research, our Head of Biology Christopher Nicholson, Ph.D., will be sharing COMPASS’ EGFRi findings on Saturday, October 14 from 12:30 – 4:00PM. More information is below. 

Abstract title: Circumventing EGFR inhibitor resistance in NSCLC using transomics

Poster number: C052

Session: Poster Session C

Session date and time: Saturday, October 14 | 12:30 pm-4:00 pm

Session location: Level 2, Exhibit Hall D

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