Targeting the EGFR/RAS/RAF signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020–2023)

ABSTRACT

Introduction

Recent years have seen significant strides in drug developmenttargeting the EGFR/RAS/RAF signaling pathway which is critical forcell growth and proliferation. Protein-protein interaction networksamong EGFR, RAS, and RAF proteins offer insights for drug discovery. This review discusses the drug design and development efforts ofinhibitors targeting these proteins over the past 3 years, detailingtheir structures, selectivity, efficacy, and combination therapy.Strategies to combat drug resistance and minimize toxicities areexplored, along with future research directions.

Area covered

This review encompasses clinical trials and patents on EGFR, KRAS,and BRAF inhibitors from 2020 to 2023, including advancements indesign and synthesis of proteolysis targeting chimeras (PROTACs) forprotein degradation.

Expert opinion

To tackle drug resistance, designing allosteric fourth-generationEGFR inhibitors is vital. Covalent, allosteric, or combinationaltherapies, along with PROTAC degraders, are key methods to addressresistance and toxicity in KRAS and BRAF inhibitors.

KEYWORDS:

• EGFR
• KRAS
• BRAF
• covalent drugs
• anticancer
• resistance
• combination therapy
• PROTACs

Article highlights

• Inhibitors of EGFR/RAS/RAF pathway have shown great promise in cancer treatment. Seven EGFR inhibitors, two KRAS G12C inhibitors, and two BRAF V600E drugs have been approved by the US FDA since 2020.

• Covalent drugs containing an α, β-unsaturated amide moiety can form covalent bonds and thus overcome drug resistance caused by EGFR T790M and L858R mutants or by KRAS G12C mutant.

• Allosteric, fourth-generation of EGFR inhibitors can overcome the resistance to third-generation EGFR inhibitors.

• Allosteric AKT inhibitors can overcome drug resistance.

• BRAF inhibitors targeting wild-type BRAF and BRAF homodimer can overcome the paradoxical ERK activation in normal cells.

• Proteolysis targeting chimeras (PROTACs) as degraders of EGFR/KRAS/BRAF were able to degrade respective proteins and overcome acquired resistance.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

R Hajjo and DA Saabah acknowledge support from the Deanship of Scientific Research at Al-Zaytoonah University of Jordan [Grant number 2020-2019/17/03].