Cytotoxic activity of KRAS inhibitors in combination with chemotherapeutics

ABSTRACT

Introduction

KRAS is the most frequently mutated oncogenic driver in pancreatic, lung, and colon cancer. Recently, KRAS inhibitors in clinical use show promising activity but most responses are partial and drug resistance develops. The use of therapeutics in combination with KRAS inhibitors are expected to improve outcomes.

Areas covered

This review describes the KRAS G12C mutation-specific inhibitors and the SOS1-targeting inhibitors that reduce the GTP-loading of wildtype and mutated KRAS. Both types of compounds reduce tumor cell proliferation in vitro and in vivo. The combinations of the various KRAS inhibitors with downstream signaling effectors, modulators of KRAS-associated metabolic alterations and chemotherapeutics are summarized.

Expert opinion

The clinical potency of mutated KRAS-specific inhibitors needs to be improved by suitable drug combinations. Inhibition of downstream signaling cascades increases toxicity and other combinations exploited comprise G12C-directed inhibitors with SOS1 inhibitors, glucose/glutamine metabolic modulators, classical chemotherapeutics, and others. The most suitable inhibitor combinations corroborated in preclinical development await clinical verification.

KEYWORDS:

• Cancer
• KRAS
• G12C
• AMG510
• MRTX849
• SOS1 inhibitor
• combination therapy

Acknowledgment

We thank B. Rath for help in the preparation of this manuscript and Dr. T. Hohenheim for enduring endorsement.

Article highlights

• KRAS mutation synthetic lethality screens

• Development of mutant-specific KRAS inhibitors

• Identification of SOS1-directed KRAS inhibitors

• Downstream signaling inhibition and KRAS

• Metabolic modulators and KRAS

• Combinations of KRAS inhibitors and chemotherapeutics

• KRAS and HSP90 inhibitors and histone modifiers

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

Additional information

Funding

This paper was not funded.