The adaptive immune system plays an important role in fighting cancer by detecting and destroying cells that have accumulated potentially dangerous mutations. The major histocompatibility complex class I (MHC class I) proteins, which are expressed on the surface of most cells in the human body, are key to this process. These complexes bind to peptides generated in the cytoplasm and shuttle these peptides to the exterior surface of the cell. Once on the surface, peptides that contain mutations can be recognized by the T cells responsible for eliminating highly mutated cells. Unfortunately, MHC class I molecules do not bind efficiently to many of the peptides containing the most common oncogenic mutations, enabling these tumors to evade immune detection. This inability of MHC class I proteins to present mutated peptides is one reason that immune checkpoint inhibitor drugs fail to help a majority of cancer patients. In this ASPIRE Award, Kevan Shokat is exploring novel strategies to enhance the binding of onco-peptides to MHC class I complexes with small molecules.
In the ASPIRE I Award, researchers in the Shokat group developed small molecules to improve MHC class I presentation of mutant peptides produced by two notoriously undruggable, cancer-causing variants of the KRAS gene—G12V and G12D. These mutations are responsible for many common and aggressive cancers including pancreatic, colorectal, and non-small cell lung cancer. The group first developed a screening platform to identify which MHC alleles would be amenable to small molecule-mediated presentation of mutated KRAS peptides through computational and experimental means. They then screened a library of FDA-approved drugs and small molecule fragments for compounds which augmented MHC presentation of KRAS onco-peptides in vitro. From those screens and a subsequent hit-to-lead chemistry campaign, they developed the lead compound 09-045B which increases the presentation of the KRAS peptides.
Now, under the ASPIRE II Award, the Shokat group will expand on the results from their ASPIRE I. First, they will determine whether 09-045B can enhance KRAS peptide presentation in vitro and in vivo using engineered cell systems and mice. They will examine whether this enhanced peptide presentation leads to more effective T cell activation and results in tumor killing. In parallel to these efforts, they will expand their established screening platform to find compounds that will enhance the MHC presentation of peptides derived from mutated p53, the most commonly mutated protein in human cancers which has stubbornly remained undruggable since its discovery. In doing so, the group will determine whether these methods will be applicable to other common cancer mutations, leading to targeted anti-cancer drugs that allow the immune system to destroy tumor cells which usually resist targeted therapies.
Vasta JD, Peacock DM, Zheng Q, Walker JA, Zhang Z, Zimprich CA, Thomas MR, Beck MT, Binkowski BF, Corona CR, Robers MB, Shokat KM. KRAS is vulnerable to reversible switch-II pocket engagement in cells. Nat Chem Biol. 2022.