Exploring KRAS Mutations in Oncology: Challenges and Opportunities - Part One

An estimated quarter of all cancer patients harbor KRAS (Kirsten Rat Sarcoma) mutations, alterations in a gene that plays a critical role in cancer development. Despite this prevalence, KRAS has long been a formidable foe in oncology, stubbornly resisting attempts to develop effective targeted therapies. However, the tide is turning. In a landmark achievement, the first two KRAS inhibitor therapies received FDA approval for non-small cell lung cancer (NSCLC) in 2021 and 2022. This marks a significant milestone in the fight against cancer, potentially ushering in a new wave of innovation of personalised medicines for patients.

This article is the first of two parts focusing on the role of KRAS mutations in tumorigenesis. The subsequent article will delve into the landscape of the recently approved drugs as well as promising candidates in the pipeline, providing insights into how drug developers are rising to the challenge in this area.

Drugging the ‘undruggable’ target

The journey toward the development of KRAS inhibitors has been fraught with challenges, primarily due to the protein's structure which initially seemed 'undruggable'. Research into KRAS began in earnest several decades ago, but it was not until 2013 that substantial progress was made by the team of Dr Kevan Shokat (1) by identifying an allosteric binding site in the KRAS G12C-mutant protein. This breakthrough was followed by intense research and development efforts, leading to the approval of the first KRAS inhibitor, LUMAKRAS (sotorasib), by the FDA in 2021. Shortly after, in 2022, a second inhibitor, KRAZATI (adagrasib), was approved, marking a pivotal moment in the targeted therapy landscape.

How KRAS mutations fuel tumorigenesis

Normally, KRAS acts like a molecular switch, turning on growth signals only when needed. However, mutations within the KRAS gene can permanently flip this switch to "on", due to the disruption of GTP hydrolysis and or enhancement of nucleotide exchange. This leads to persistent downstream signaling of pathways such as MAPK and PI3K, ultimately leading to uncontrolled cell proliferation and tumor formation. 

The Prevalence of KRAS Mutations Across Tumor Types

KRAS mutations occur in a wide range of cancers, with varying frequencies and predominant mutation subtypes. Leading tumor types include (2): 

• NSCLC: KRAS mutation prevalence 23%, common subtype G12C
• Pancreatic cancer: KRAS mutation prevalence 91%, common subtypes G12D and G12V
• Colorectal cancer: KRAS mutation prevalence 30-44%, common subtypes G12D and G13D

An additional complication is that KRAS mutations often co-exist with other mutations, that may in turn affect the functioning of the KRAS mutations. For example, a study in NSCLC revealed that approximately 54% of subjects had at least one additional co-mutation such as mutations in TP53 and STK11 in NSCLC (3).

Impact of KRAS mutations on the tumor microenvironment and immune response

KRAS mutations also modulate the tumor microenvironment, impacting immune surveillance and response. These mutations can lead to an immunosuppressive microenvironment by recruiting regulatory T cells and myeloid-derived suppressor cells, while also reducing the presentation of tumor antigens, thus evading immune detection. Furthermore, different types of KRAS mutations and co-mutations appear to limit the effectiveness of immune checkpoint inhibitors. For example, STIK11 and KEAP1 mutations along with KRAS mutations appears to result in a poor response to PD(L)1 therapy in lung adenocarcinoma (4).

The threat of resistance

A major challenge in developing drugs to inhibit KRAS mutations is resistance, which can be of the following types:

1. Innate resistance: As we shall see in the next article, phase 2 trials for the approved KRAS inhibitors saw objective responses in less than 50% of patients, suggesting significant innate resistance mechanisms. Potential causes could include notable heterogeneity in the mutations themselves and or concurrent mutations. 
2. Acquired or adaptive resistance: These can include on-target resistance (further KRAS mutations), up- or down-stream bypass mechanisms, changes in the microtumor environment and histological changes. 

Conclusion

Whilst enormous strides have been made in developing drugs to target KRAS mutations, there remain challenging obstacles to improve patient outcomes such as resistance and complexities associated with variations in mutations, the tumor microenvironment and coexisting mutations. Stay tuned for part two, where we'll explore how drug developers are addressing these challenges and advancing KRAS-targeted therapies.

References

(1) Ostrem et al, K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions, Nature, 2013

(2) Parikh et al, Drugging KRAS: Current perspectives and state-of-the-art review, J Hematology and Oncology, 2022

(3) Scheffler et al, K-ras mutation subtypes in NSCLC and associated co-occurring mutations in other oncogenic pathways, J Thora Oncol, 2019

(4) Ricciuti et al, Diminished efficacy of programmed death-(Ligand)1 inhibition in STIK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status, J Thora Oncol, 2022

If you are interested in discussing any of the issues above for your company/drug development program, please contact me through my Linkedin profile. Please note, I have no conflicts of interest in the production of this article.