The beginning of the end for KRAS Cancers

The KRAS protein is a central node in one of the most important signalling networks within our cells. Known as ‘the beating heart of cancer’, it beats between two states: mostly ‘off’ in healthy cells and switching to ‘on’ in cancer cells. The challenge with finding effective treatments for KRAS-driven cancers is three-fold: not only do we need to find a way to switch KRAS off but we also need to keep it switched off and avoid the emergence of resistance. As yet, there are no drugs approved against RAS proteins, of which KRAS is the most important member.

What really inspired me and the whole Boehringer Ingelheim oncology team to take KRAS on was the sheer numbers of cancer patients that could benefit if we succeeded. Drugging KRAS is first and foremost a chemistry problem. As a chemist, I couldn’t accept that KRAS was an unsolvable problem. That was back in 2012; today no-one calls KRAS undruggable anymore.

The first thing we did - and continue to do - was to take a systematic, blanket approach to KRAS. This level of commitment sets us apart from others. Our intention was never to have just one or two KRAS projects. Instead, we set the strategic goal to establish a cluster of KRAS projects. The cluster has been building year on year, with existing projects sparking new ones and chemistry breakthroughs opening up opportunities in biology and vice versa.  

Our guiding principle as we set out was, “Let’s inhibit KRAS as directly and specifically as possible.” This sounds easy but there’s a catch. KRAS belongs to a class of drug targets where, instead of turning an enzyme or protein off as in the ‘key in the lock’ model, we have to stop two proteins coming together by finding protein-protein interaction (PPI) inhibitors, more like a screwdriver prising a door away from the frame. This class of proteins lacks the deep pockets that we chemists need to make drugs, so we needed to apply non-traditional approaches to be successful. 

A technology called fragment-based drug discovery, which involves probing disease-causing proteins with fragments of molecular ‘keys’ rather than complete ‘keys’, is the way to go to drug RAS and other such targets. But working with fragments requires a different mindset and skillset; you can’t do fragment-based drug discovery half-heartedly. That’s why we collaborated early in our endeavour with Professor Stephen Fesik, the pioneer of fragment-based drug discovery, at Vanderbilt University. For almost a decade now every chemist in our oncology team has dedicated themselves to fragment-based approaches.

And that was the trick. Suddenly, working with fragments we discovered that KRAS and every other PPI target that we looked at, did, indeed, have pockets, all be it well hidden, shallow pockets. This was the ‘foot in the door’ and gave us a starting point with KRAS. 

And a second technology, alongside fragments, was instrumental in building our capabilities to successfully drug KRAS: protein crystallography, which uses X-rays to give three-dimensional images of how drug candidates fit into their ‘locks’. We’ve optimised our KRAS crystal systems to such an extent that we can now get a ‘3D-KRAS photo’ of almost every compound we make. These 3D-photographs enable our chemists to know exactly where every atom needs to be placed to make a KRAS drug. This is important because the KRAS fragments we start out with need to be improved a million-fold before they become potent drug molecules. 

Stopping feedback with SOS1 inhibition

Cell signalling networks in cancer are extremely resilient. When we treat cancer cells with KRAS inhibitors, the KRAS signalling is shut down at the drug target and the ‘volume’ of signalling across the whole pathway is turned down. But, after a matter of only a few hours hours, the ‘volume’ goes up somewhere else in the network and signalling is restored. Termed feedback, this also needs to be addressed if we are to treat KRAS cancers effectively.

So, we’re increasingly adding to our armament, of molecules, ones that block feedback in KRAS-driven cancer cells. And we’ve found an ideal target in SOS1, a protein named Son of Sevenless 1, which is responsible not only for turning KRAS on but is also the key feedback node in KRAS signalling.  If KRAS is the ‘beating heart’ of cancer, then SOS is its’ pacemaker. KRAS can’t ‘beat’ without SOS. 

By selectively inhibiting SOS1, one of the two types of SOS, we are simultaneously slowing KRAS beating and blocking feedback. With feedback blocked, we are now able to permanently shut down KRAS signalling by combining SOS1 inhibitors with inhibitors of other key proteins in the RAS signalling pathway, such as MEK.

Selective inhibition of SOS1, alone or in combination with MEK inhibition, is a therapeutic concept with the potential to treat all KRAS cancers irrespective of the KRAS-mutation type: a pan-KRAS inhibitor. And we’ve found that’s exactly what our SOS1 inhibitors can do. In contrast to KRASG12C inhibitors, our SOS1 inhibitors block the interaction of SOS1 with the inactive form of KRAS in a manner that is independent of KRAS mutation status. They are orally bioavailable and well-tolerated, and treatment leads to KRAS pathway inhibition which translates into tumor stasis in the laboratory. Even more exciting is that we see significant tumor shrinkage when our SOS1 inhibitor is combined with a MEK inhibitor.

Looking to the future

It’s a very, very exciting phase in KRAS research. We’ve now got a large portfolio of KRAS programs with almost everyone in the Vienna team working or having worked on KRAS in one way or another, not to mention our many collaborators around the world. Digging deeper into understanding KRAS by leveraging our growing expertise with cutting-edge chemical and biological technologies means that new opportunities keep presenting themselves. 

The task that we are committed to is enormous: directly targeting KRAS, blocking feedback and ultimately getting ahead of resistance. It might take a generation to complete the task but 2019 marks an important milestone as the year that the first patients received experimental KRASG12C and pan-KRAS inhibitors, almost 40 years after the discovery of KRAS.  Boehringer Ingelheim is a family-owned company that thinks in generations. We have the long-term vision and scientific persistence to complete this task and put an end to KRAS cancers.