Military commanders generally have one clear aim when they plot how to achieve their objectives: identity the enemy’s Achilles heel (any small vulnerabilities in its amour) and then exploit them to maximum effect.
When it comes to cancer, scientists have spent decades trying to find any small weaknesses in mutated human genes, known as oncogenes, which spur malignant tumour growth.
One of the biggest focus areas has been the RAS family of genes. Their mutations not only lie behind about one quarter of all cancers, but some of the deadliest of all.
The most prevalent is the KRAS gene, which drives more than: 90% of pancreatic adenocarinomas (the most common type of pancreatic cancer), 40% of colorectal cancer and about 30% of non-small cell lung (NSCLC), which accounts for up to 85% of all lung cancers. It is also less frequently responsible for endometrial and ovarian cancer.
This gene, or Kirsten rat sarcoma virus to give it its full name, was named after Werner Kirsten, the German-American cancer researcher who first discovered it in cultured rodent cancer cells during the 1960s. It was isolated in human cancer cells for the first time in 1982.
What makes the KRAS gene so dangerous is the pivotal role it plays in cell growth, proliferation and death. Its main function lies in providing instructions to create a protein, which acts like master switch, sending signals to a cell’s nucleus as it flips between on and off mode.
Tumours develop when the switch gets permanently stuck in on mode (after binding to another molecule called GTP). This prompts uncontrollable cellular growth.
Identifying genetic mutations and understanding the role they play in driving cancer was the first key step. However, finding a weakness, which could then provide an opening for therapeutic drugs has proven to be a whole lot harder.
The biggest challenge has been the KRAS protein’s round, smooth shape. Its structural biology means that there isn’t an obvious spot for therapeutic drugs to latch onto, or nestle into.
Scientists began to openly debate whether cancers with KRAS mutations were “undruggable.” In Western countries, KRAS became popularly known as cancer’s Death Star, after the moon-shaped battleship, which was able to destroy entire planets in the Star Wars film franchise.
However, the Death Star was eventually blown up after the film’s heroes discovered that it did have one structural weakness – a small exhaust port they could fire a missile into, which then triggered a chain reactor throughout the entire ship.
And in 2013, an equivalent spot was discovered within the KRAS protein,a crevice hidden under the protein’s surface at a particular hotspot where mutations take place.
Accessing this crevice provided a suitable entry point for a drug, which could permanently bind itself to the mutant KRAS protein and de-activate it.
The advent of G12C inhibitors
That first drug is called Lumakras (sotorasib) and it targets a very specific KRAS mutation called G12C. Its developer – the US biotech Amgen – also achieved approval after the fastest clinical trial in its history.
This came in May 2021, when the US Food & Drug Administration (FDA) approved Lumakras through its fast track programme for treatment against KRAS G12C-mutated advanced NSCLC. European Union approval followed in January 2022.
Results from Phase 2 of Amgen’s CodeBreaK 100 study showed that Lumakras could curb tumour growth in over 80% of the 126 trial participants with KRAS G12C-related advanced NSCLC. It was able to shrink tumours in just over a third.
Amgen has also presented data for colorectal and pancreatic patients.
In February 2022, for example, it released efficacy data for Phase 1/2 trials with 38 pancreatic patients who were at an advanced stage of the disease and had at least two previous treatments behind them. The drug achieved an 84% disease control rate.
Other developers including Novartis and Mirati Therapeutics are not far behind with G12C inhibitors of their own. In February 2022, Mirati submitted a drug for FDA approval to treat advanced NSCLC and colorectal cancer.
The US biotech hopes that its drug (adagrasib) will have an edge thanks to promising results as a combination therapy when taken alongside immunotherapy drugs like Keytruda (pembrolizumab). This latter group of drugs are known as checkpoint inhibitors because their job is to block proteins, which stop the immune system from attacking cancer cells.
Last year, Mirati released Phase 1b data from its KRYSTAL-1 study of eight patients with KRAS G12C-mutated NSCLC. It achieved a 100% disease control rate after patients received adagrasib and Keytruda. Tumours shrank between 37% and 92% in size.
Progress towards G12D inhibitors
Advances in developing GC12C inhibitors have encouraged biotechs to tackle an even more prevalent mutation, G12D. This occurs in 36% of all KRAS-mutated cancers compared to 14% for G12C and 23% for a third mutation called G12V.
It is the biggest target for pancreatic cancer, whereas G12C is far more common in NSCLC (occurring in 13% of all cancers).
Mirati Therapeutics has a G12D inhibitor (MRTX1133) in pre-clinical development, while a Chinese biotech called Jacobio Pharmaceuticals has one called JAB-22000.
A third US biotech called Revolution Medicines also recently said that it’s on track to file an investigational new drug application to start a Phase I trial for a RAS inhibitor called RMC-6236. This tackles all three of the KRAS mutations.
Its pre-clinical research showed anti-tumour activity against colorectal, lung and pancreatic cancer.
It also deploys a novel technology to deal with the challenge of finding sites on the KRAS protein for drugs to lock onto. It does this by creating a new pocket through linking the mutant KRAS protein with a chaperone protein.
Why are KRAS mutations so dangerous?
This February, scientists also made further headway understanding what makes KRAS mutations so lethal. They discovered that it’s not just about the way the protein encourages excessive cell growth.
Researchers at Duke University and the Terasaki Institute in the US discovered that KRAS mutations also rearrange a cell’s chromatin (substances within chromosomes consisting of DNA and proteins).
When this happens, tissue cells revert to a nascent stem-like state and mistakenly start creating new tissue via a protein called AP-1, which form into tumours. The researchers concluded that AP-1 inhibitor drugs might offer a new treatment route to handle KRAS mutation driven tumours.
For many decades, patients with lung and pancreatic cancers have suffered from poor prognoses. A mutated KRAS biomarker is not one that any cancer patient wants to hear that they have.
But there is now hope. When this crucial gene turns to the dark side, there should be increasingly more drugs to stop it in its tracks.