Researchers at Boehringer Ingelheim are seeking to eradicate one of the key drivers of cancer – the KRAS protein. New partnerships are intended to enable combination treatments that help to tackle different mutations.
Scientists have great respect for KRAS. Due to its importance, they refer to this protein from the RAS family as “the beating heart of cancer”. KRAS promotes the growth of cancer cells; it is the most frequently mutated cancer-causing gene – and it is responsible for virtually every type of pancreatic cancer as well as many forms of intestinal and lung cancer. Moreover, even though KRAS’ significance for cancer has long been understood, hardly anyone had dared to combat the protein. It was thought to be hopeless – KRAS appeared not to have any sites that medicine molecules could bind onto, and it was considered untreatable.
“For nearly 40 years, every attempt to develop inhibitors has failed,” says Prof. Dr. Norbert Kraut, Global Head of Cancer Research at Boehringer Ingelheim. “However, there are now two promising approaches: On the one hand, binding KRAS directly. And on the other, blocking its activation through SOS1.”
Not all KRAS proteins are alike. KRAS occurs in many mutant forms in the cell: Nine different KRAS mutants cause over 90 percent of all KRAS-driven cancers. One form is the driver mutation KRAS G12C, which occurs in around 15 percent of non-small cell lung cancers. Some pharmaceutical companies have already developed molecules for this that have yielded positive results in early clinical studies. They freeze KRAS in off mode. Boehringer Ingelheim is also taking part in this race. Its proprietary G12C inhibitor is set to undergo clinical testing in 2021. “We are not the first to do this, but we believe we have a very promising product,” says Kraut. This inhibitor makes use of a binding site which Boehringer Ingelheim has identified by means of small pieces of drug molecules known as “fragments”.
KRAS G12C is only the third most common form of mutated KRAS. The mutations KRAS G12D and KRAS G12V account for more than half of the total number of cancers caused by KRAS. Unlike in the case of G12C, no promising pockets or locks for substance molecules to attach themselves to have been identified for these mutations so far.
BI 1701963 – the pan-KRAS inhibitor of Boehringer Ingelheim – may be helpful in dealing with all of these mutations. It prevents KRAS from being switched on by blocking the activator protein SOS1. “KRAS cannot strike without SOS1,” Kraut notes. The combination of SOS1 inhibitors with other inhibitors might make it possible to inhibit KRAS permanently – and in virtually all of its mutations. “The molecule BI 1701963 was developed with the goal of inhibiting a wide range of oncogenic KRAS variants,” Kraut remarks. Pre-clinical data has confirmed that the pan-KRAS inhibitor blocks tumor growth in many of the G12 and G13 KRAS gene mutations tested.
Boehringer Ingelheim is working with partners across the life science community in order to achieve faster progress in researching such combination treatments. In September 2019, Boehringer Ingelheim expanded its KRAS cancer program through a partnership with the Indian pharmaceutical company Lupin Limited; Boehringer Ingelheim has in-licensed an MEK inhibitor as one of several potential SOS1 combination partners. MEK is another key protein in the RAS signal pathway.
Moreover, in September 2020, Boehringer Ingelheim announced its clinical partnership with the US biotech company Mirati Therapeutics in order to test a combination of the pan-KRAS inhibitor of Boehringer Ingelheim and Mirati’s G12C KRAS inhibitor adagrasib (MRTX849). The potential of this combination as a more effective treatment option for people with lung or colon cancer with a KRAS G12C mutation will be examined in an initial Phase I study.
“We consider this a win-win situation,” says Kraut in reference to the partnership. Both partners are convinced that the interaction of their inhibitors will benefit the patient – and that their cooperation provides a fast way to achieve a genuine improvement in the therapy options. “In pre-clinical studies, we have seen that many of the KRAS G12C-driven tumors treated shrink; that is a very positive starting point.”
The partnership with Mirati will build on the longterm collaboration of Boehringer Ingelheim with the MD Anderson Cancer Center at the University of Texas, one of the largest cancer clinics in the United States. American scientists are seen as world leaders in cancer research, their expertise includes a broad range of study and patient data. They could be able to conduct potential clinical studies on behalf of the new partners. “We don’t enter into partnerships at random. Our partnerships build on one another; they supplement one another, and they thus all support our goal of achieving faster and genuine progress in fighting cancer,” says Kraut.
More partnerships may follow in the near future: In its annual strategy review, the companies board of managing directors announced that, in the medium term, Boehringer Ingelheim intends to invest even more strongly in research and, in particular, in its oncology pipeline. “That means we will be able to conduct more research on a broad front and enter into further partnerships,” Kraut comments. “And all of that with the goal of achieving a decisive improvement of patients’ health.”