Multiple initiatives to conquer KRAS G12C inhibitor resistance from the perspective of clinical therapy

ABSTRACT

Introduction

KRAS G12C targeted covalent inhibitors for cancer therapy are revolutionary. However, resistance to KRAS G12C inhibitors in clinical trials is a proven fact.

Areas covered

The authors focus on providing coverage and emphasizing the strategy of conquering KRAS G12C inhibitor resistance from the perspective of clinical therapy. The authors also provide the readers with their expert perspectives for future development.

Expert opinion

It is essential to improve the therapeutic effect and achieve long-term disease control through accumulating rapid exploration of drug resistance mechanisms in preclinical trials and developing rational combination dosing approaches from clinical practice. Our presentation of the perspective provides insights into drug resistance in this groundbreaking area of research.

KEYWORDS:

• KRAS G12C
• AMG 510
• MRTX 849
• targeted therapy
• drug resistance

Article highlights

• Clinical resistance versus adagrasib and sotorasib suggests the necessity for discovering new types of KRAS G12C inhibitors and innovating pan-KRAS therapy approaches.

• Powerful rationale enables combining KRAS G12C inhibitors with other treatments.

• Promising combination therapies with MAPK or PI3K pathway inhibitors targeting EGFR, SHP2, SOS1, MEK1, ERK, PI3K, and mTOR pronounce potential to tackle drug resistance.

• The excellent paradigms presented in the article demonstrate the feasibility of overcoming resistance to KRAS G12C inhibitors.

Declaration of interest

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.

Data availability statement

Data will be made available on request.

Additional information

Funding

The authors are funded by the Macao Young Scholars Program (AM201926 and AM2020018), the Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery (Grant no. 001/2020/ALC) and regular grants (File no. 0096/2018/A3 & 0111/2020/A3, 0015/2019/AMJ, 0056/2020/AMJ, and 0114/2020/A3) supported by Macao Science and Technology Development Fund, Macau (S.A.R.) China.