Drugging the undruggable mutation

FDA approves Sotorasib, first drug targeting KRAS G12C.

In the decades since its discovery, a well-known mutation KRAS G12C has earned the title of “undruggable mutation”. Despite the fact that it’s one of the most prevalent mutations in human cancers and the subject of extensive research, it has proved to be extremely challenging as a drug target. However, a sequence of breakthroughs between 2013 and 2016 opened the door to a family of small molecules capable of inhibiting the oncogenic properties of the mutant protein. In 2021, a new drug, Sotorasib, became the first FDA-approved drug targeting the KRAS G12C mutation. In this post we’ll go through the story of the discoveries that led to this achievement.

KRAS: a Ubiquitous Signalling Protein

Cell signalling pathways provide cells with the ability to receive, process, and act upon the information they receive from their environment. It is these signalling pathways that ultimately control different cellular programs like growth, differentiation, and cell death. Disruption of these pathways can promote the development of cancer.

The KRAS gene codes for the K-Ras protein, a ubiquitous cell signalling protein present in many different cell types. The K-Ras protein belongs to the GTPase family of signalling proteins, acting as a molecular “on/off” switch. The active (“on”) state is characterized by binding of GTP and the inactive (off) state by binding of GDP to the K-Ras protein. In its active state, K-Ras participates in cell signaling pathways by recruiting other signalling molecules which activate downstream pathways.

Like other GTPases, the switch between active and inactive states of the K-Ras protein is regulated by the hydrolysis of GTP which is catalyzed by GTPase activating proteins (GAP). The hydrolysis of a K-Ras bound GTP molecule leaves behind a bound GDP molecule which effectively turns the K-Ras switch off until guanosine exchange factors (GEFs) can displace the bound GDP. A cell’s ability to control the on or off state of the K-Ras protein is therefore critical for its normal function. KRAS mutants have long been recognized as oncogenes are the most common activating mutation in human cancers.

The Undruggable Mutant

One of the most common mutations in KRAS is known as G12C. This single-nucleotide change replaces the glycine amino acid at position 12 of the K-Ras protein for cysteine. Since its discovery three decades ago, the KRAS G12C mutation has been extensively studied. It’s known to be a common driver of various types of cancer, most notably non-small cell lung cancer. Its presence is also known to have a negative effect on responsiveness to treatments in other cancers driven by other mutations. The molecular pathology of the KRAS G12C stems from the fact that the normal regulatory step of GTP hydrolysis is significantly reduced leading to high and sustained levels of RAS signalling.

In order to inhibit this mutant protein, small molecules capable of selectively inhibiting the activity of the oncogenic mutant protein would be required. Despite decades of efforts, however, the complexity and location of the switch region pockets appeared impossible to target, earning the KRAS G12C mutation the title of the undruggable mutation.

Finally, a Breakthrough

Given the prevalence of KRAS G12C and its established role in etiology of cancer, efforts to develop targeted inhibitors continued until a breakthrough finally came in 2013 from a research group at the University of California, San Francisco. The group reported the effectiveness of a number of small molecules in inhibiting the always-on, mutant K-ras protein without affecting the wild-type protein. The key discovery that enabled this was the identification of a previously unknown molecular feature in the mutant K-Ras, dubbed the “switch-II pocket”, to which these new inhibitors could bind.

A few years later, in 2016, another group of researchers from the MSKCC and Wellspring Biosciences, reported a novel compound ARS-853 with high affinity to the same newly discovered binding pocket in K-Ras G12C. This new compound relied on a novel mechanism that the group had discovered about the protein’s hydrolytic behavior. Instead of inhibiting the oncogenic signalling behavior of active, GTP-bound K-Ras, this new compound binds to the inactive, GDP-bound protein and trapping it in its inactive state.

This was huge! We had finally identified a feasible strategy for targeting one of the most common somatic mutations in human cancer. The following years saw a rapid growth in our understanding of the newfound switch-II pocket, the dynamics of K-Ras G12C hydrolytic activity, and the effectiveness of different novel compounds in managing the pathogenic behavior of mutant K-Ras.

Path to Clinical Approval

Between 2016 and 2020, the journey that began with ARS-853 continued with more effective targeted drugs, ARS-1612 (2018), MRTX849 (2019), and AMG 150. By 2020, clinical trials for the Amgen developed drug AMG 150, dubbed Sotorasib, were on the way. The early trials focused on cancer patients with advanced solid tumours, notably non-small cell lung cancer (NSCLC), harbouring the KRAS G12C mutation. In a phase 1 trial, 129 patients with NSLC, colorectal, and other cancers were included. Even though about half of the patients showed some treatment-related adverse effects, the majority of patients, especially those in the NSCLC group (88%) showed an objective response to the treatment.

A phase 2 trial focused exclusively on NSCLC patients, most of whom had already received other existing treatments. In the 126 patient cohort, the new treatment showed durable disease control in most patients (80%) and an objective response in over a third (37%).

While more clinical trials for Sotorasib treatment are still ongoing, and recruiting patients, on May 28, 2021, the FDA granted accelerated approval to Sotorasib for KRAS mutant NSCLC. This made Sotorasib the first approved treatment targeting KRAS G12C, the mutation known for years as the undruggable mutation.