A Unique Treatment Approach to Stopping KRAS Mutations

KRAS Mutations: KRAS MutationsIf there was a poster depicting some of the world's most-wanted cancer-causing culprits, the KRAS family of mutant genes certainly would be given a position of prominence, eluding capture even when thought to be finally ensnared by a molecular trap earlier this decade. Now, a team of researchers from California and New York has designed a nature-inspired small “molecular glue” that binds to and reshapes the surface of cyclophilin A (CypA), a cellular “chaperone” that typically shields KRAS from harmful proteins that might hinder critical processes, such as protein folding. According to a study published in the journal Science, the newly reshaped chaperone bound selectively and tightly to the active or “on” state of KRASG12C—one of the more notorious members of the mutant KRAS family in a three-way complex (CypA:drug:KRASG12C)—shutting down its cancer-causing signals (2023; doi: 10.1126/science.adj1001). The resulting triplex shrank tumors in preclinical models of non-small cell lung cancer (NSCLC) and colorectal cancer—two cancer types with frequent KRAS mutations. In the same issue of Science, Jun O. Liu, PhD, Co-Director of Cancer Chemical and Structural Biology with the Johns Hopkins Kimmel Comprehensive Cancer Center in Baltimore, said the new strategy described in this study represented “an unprecedented mode of action by a small molecule.” According to Liu, who did not participate in this study, “With the seemingly untouchable active states of KRASG12C conquered, it will be interesting to explore whether these approaches can be applied to other KRAS mutants, small GTPases, trimeric G proteins, and even other classes of ‘undruggable’ targets.” Clinical trials are now underway to test novel KRAS inhibitors based on this research in patients with advanced mutant solid cancers, including NSCLC and colorectal cancer. The Role of KRAS Typically, the KRAS gene—initially discovered in 1982—serves as an information hub for signals that lead to cell growth, doing so by breaking down the molecule guanosine triphosphate (GTP) into another called guanosine diphosphate (GDP). In its active state, KRAS is bound to GTP and, conversely, KRAS is bound to GDP in its inactive state. When mutated, KRAS signals get stuck in the active state, leading to continuous and uncontrollable cell growth—the hallmark of cancer. For several decades, KRAS mutants were considered “undruggable” owing to their considerably smooth and shallow surface, making it difficult to find a druggable docking site for a small molecular inhibitor. The only pocket on the surface of KRAS that might bind with a small molecule is the GTP-binding pocket. However, targeting this pocket also has proven quite difficult since GTP generally monopolizes this sole pocket on the surface of KRAS. As the focus of this study, KRASG12C is a single-point mutation with a glycine-to-cysteine amino acid substitution in codon 12. This substitution favors the activated or “on” state of KRAS. Earlier this decade, inhibitors were designed that selectively targeted the GDP-bound inactive state of the KRASG12C, generating excitement about their clinical promise for the treatment of advanced NSCLC with KRASG12C mutations. Considered a milestone or watershed moment for the treatment of lung cancer, the FDA approved the first two inhibitors for cancers with KRASG12C mutations—sotorasib and adagrasib. Both drugs initially brought significant survival benefit to patients with NSCLC. Unfortunately, however, most who responded to the drug eventually developed resistance to it and their tumors started to regrow. So, once again, the KRASG12C mutation appeared to be “undruggable.” Disappointed, physicians and researchers alike renewed their search for other options, perhaps something novel that would inhibit the oncogene in its active GTP state that is directly responsible for driving oncogenic signaling. Like many other solutions in science, inspiration came from nature. New Research “The study takes its inspiration from the mechanism of some natural products,” said Piro Lito, MD, PhD, a physician-scientist in the Human Oncology & Pathogenesis Program at Memorial Sloan Kettering Cancer Center in New York, and the study's other co-principal investigator. “Specifically, the drug candidates were derived from a natural product called sanglifehrin A, which interacts with a multipurpose cellular protein called cyclophilin A.” Sanglifehrin A, isolated and purified from actinobacteria—the main source of antibiotic classes in clinical use—is an immunosuppressant, capable of inhibiting CypA binding in nature. Overexpression of CypA has a major role in various pathological conditions, such as inflammatory reactions and cartilage destruction in rheumatoid arthritis, progression of inflammatory diseases in the lung, and growth and spread of cancer. By exploiting what has evolved in nature, the researchers hypothesized that they could create a modified version of sanglifehrin A that's capable of binding to and reshaping the surface of the CypA that serves as a chaperone for KRASG12C. In so doing, they believed their long sought-after nemesis could finally be successfully targeted and locked up. The nature-inspired product has been referred to as a “molecular glue,” defined as a small molecule that induces an interaction between two proteins that do not normally interact with one another. The result here was a triplex (CypA:drug:KRASG12C) that exploits the surfaces of two adjacent proteins—the chaperone protein and the cysteine residue in the active state of the target mutant KRAS—to form a new binding site. “By modifying the shape of the natural product (sanglifehrin A), the team was able to sculpt the surface of cyclophilin A in a way that it enables it to recognize the active state of mutant KRAS,” Lito explained. With the active state of the mutation trapped by the triplex, signals from the mutated gene were blocked in preclinical trials, effectively shutting down the cancer-causing activity of KRASG12C. A clinical version of the small molecule inhibitor, called RMC-6291, is now in Phase I/Ib trials in patients with select KRASG12C mutations. The research team already has developed two additional RAS(ON) inhibitors, also now in clinical trials—RMC-6236 for patients with advanced solid tumors harboring select KRASG12 mutations and a mutant allele specific-inhibitor, RMC-9805, targeting KRASG12D (ON), the most common KRAS mutations in patients with pancreatic or colorectal cancer. Warren Froelich is a contributing writer.