Best session of ESMO (for me anyway)

Treating KRAS-Mutated NSCLC: ESMO 2024 Session and the Evolution of KRAS as a Drug Target on Day One

But first - let's have an Introduction to KRAS: From undruggable to druggable to lots of druggables

KRAS Overview and History KRAS (Kirsten Rat Sarcoma) is one of the most frequently mutated oncogenes in human cancers, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma.

KRAS is a gene that makes a protein involved in cell growth and division. Think of it as a tiny on/off switch (like a light switch) inside cells that controls how they grow. Normally, KRAS helps cells grow when needed and turns off when it's not. But sometimes, KRAS gets mutated (changed) and stuck in the "on" position, causing cells to grow uncontrollably, which can lead to cancer. The on/off should be in a nice rhythm like a cellular heart beat - but here is where we run into problems.

The Kirsten Rat Connection:

KRAS got its name from the "Kirsten rat sarcoma virus," which is where the gene was first discovered. A scientist named Werner Kirsten found this virus in rats, and it could cause cancer.

So, KRAS is named after the rat virus that helped us understand how this powerful gene can drive cancer growth.

Despite being identified as a critical driver of cancer progression over four decades ago, KRAS was considered an "undruggable" target for many years due to its biochemical properties.

Evolution of KRAS as a Drug Target KRAS proteins, specifically KRAS G12C in the first case, were historically difficult to target due to the lack of druggable binding pockets (and their high affinity for GTP).

Imagine climbing a rock without any hand or foot holds - it would be difficult to hold on right ? This is the same for drugs which need texture, cracks (chemical hand or footholds) to bind to.

However, the discovery of a novel allosteric (see below) site in the KRAS G12C mutant, which replaces glycine with a reactive cysteine (these are amino acids), marked a breakthrough. Researchers exploited this site using covalent inhibitors that irreversibly bind to the mutant protein, effectively "locking" it in its inactive state. This led to the development of two key drugs: Sotorasib (AMG510) and Adagrasib (MRTX849), both of which are KRAS G12C-specific inhibitors approved for treating advanced KRAS G12C-mutated NSCLC - there are now MANY more compounds in development across KRAS.

Allosteric targeting is like hitting a switch that controls the main function of a protein, but instead of hitting the main button, you push a hidden button on the side. This hidden spot, called an allosteric site, changes the protein’s shape and stops it from working normally.

KRAS G12C Mutation: The Turning Point KRAS G12C is a specific mutation where glycine (G) at position 12 is substituted with cysteine (C). This mutation is particularly common in lung cancer and is associated with smoking. The mutation traps KRAS in an active, GTP-bound state, continuously sending growth signals that drive cancer progression. Targeting KRAS G12C with inhibitors such as Sotorasib and Adagrasib has been transformative, as these drugs selectively target the mutant form of KRAS, sparing wild-type KRAS and minimizing off-target effects.

The journey of KRAS from "undruggable" to "druggable" underscores the importance of innovative drug design and highlights the potential for expanding targeted therapies to more cancer patients with KRAS-driven tumours - now here is the ESMO session broken down.

• Herzberg, B.O., and Manji, G.A., 2023. KRAS: Druggable at Last. The Oncologist, 28, pp. 283–286. Available at: https://doi.org/10.1093/oncolo/oyad014.
• Huang, L., Guo, Z., Wang, F., and Fu, L., 2021. KRAS mutation: from undruggable to druggable in cancer. Signal Transduction and Targeted Therapy, 6, p. 386. Available at: https://doi.org/10.1038/s41392-021-00780-4.

ESMO 2024 Session: Treating KRAS-Mutated NSCLC

Session Overview The ESMO 2024 session "Treating KRAS-mutated NSCLC" on Day 1 from 14:00-15:30 featured expert discussions on the latest advancements and challenges in treating KRAS-mutated NSCLC.

1. Natasha Leigh (14:00 - 14:20) Targeted Therapies): Highlighted the emergence of G12C inhibitors, describing their mechanisms and challenges, such as resistance development and the impact of co-mutations like STK11 and KEAP1. She discussed the approved G12C inhibitors, Adagrasib and Sotorasib, and emphasized the importance of testing and proper subtyping of KRAS mutations to guide therapy choices.
2. Colin Lindsay (14:20-14:40) - Non-G12C Mutations: Future Perspectives): Focused on other KRAS mutations like G12D and G12V, which have distinct biochemical properties that complicate treatment. He discussed new inhibitors targeting these mutations and the potential for combination strategies.
3. Mark Awad (14:40-1500) - Resistance and Sequencing): Addressed the various resistance mechanisms to KRAS inhibitors, including secondary mutations and pathway reactivation. Highlighted the complexity of overcoming resistance, especially when multiple mutations occur simultaneously.
4. Jarushka Naidoo (15:00-15:20) - Combinations with IO): Explored combining KRAS inhibitors with immunotherapy, highlighting the challenges of toxicity, particularly hepatitis and diarrhoea. Naidoo stressed the importance of translational efforts to better understand and manage these toxicities
5. Q/A

Terri Conneran 's Question from KRAS Kickers Terry from KRAS Kickers asked about the side effects' duration and any ongoing data collection on steroid use implications in treatment results. The panel acknowledged the significant impact of side effects, particularly the prolonged nature of immune-related toxicities like hepatitis. There is an ongoing effort to better understand these toxicities, including steroid use, which can influence treatment outcomes and management strategies. The session emphasised the need for dedicated studies to track these effects comprehensively, especially in sequential and combination treatment settings.

What are the next steps ?

• Conduct more research on toxicity management and develop preclinical models to better understand and predict side effects.
• Continue clinical trials combining KRAS inhibitors with immunotherapy and chemotherapy.
• Develop composite immunotherapy scores to identify patients who will benefit from immunotherapy.
• Expand KRAS testing and ensure pathologists are aware of the need for proper subtyping.

We have learnt so much in 40 years, especially the last 5.