Selected Articles from This Issue

p53, known as the “guardian of the genome”, is one of the most important tumor suppressors. Amplification of MDM2, a key negative regulator, inactivates p53 and promotes tumorigenesis. Accordingly, compounds that disrupt the MDM2–p53 interaction represent a promising therapeutic approach to restore p53 tumor suppressor activity in patients with TP53 wild-type tumors. Here, Sini and colleagues present the discovery and characterization of brigimadlin (BI 907828), a novel, investigational MDM2–p53 antagonist. Brigimadlin treatment restored p53 activity and led to apoptosis induction and tumor reduction in preclinical models of TP53 wild-type, MDM2-amplified cancers. Brigimadlin demonstrated favorable pharmacokinetic properties that allow intermittent dosing to mitigate on-target toxicities. These data support clinical investigation of brigimadlin in MDM2-amplified cancers.KRAS is the most frequently dysregulated oncogene with high prevalence in lung, colorectal and pancreatic cancers. SOS1 is a key activator of KRAS and facilitates the conversion of inactive KRAS to active KRAS. Here, Xiao and colleagues identified and characterized a potent and selective SOS1 inhibitor, RGT-018, that suppressed KRAS signaling and tumor growth as a single agent or in combination with targeted agents. Furthermore, in combination with targeted therapies, RGT-018 overcame the resistance to the approved KRASG12C inhibitors caused by clinically acquired KRAS mutations. RGT-018 displayed promising pharmacological properties as a candidate for clinical development to treat KRAS-driven tumors.Several cancers, such as pancreatic, lung and colorectal, are frequently driven by RAS mutations and have been shown to be responsive to CDK4/6 and MEK inhibition. Here, Wu and colleagues from Roswell Park Comprehensive Cancer Center demonstrate that the pharmacological activation of RB with combined CDK4/6 and MEK inhibition unleashes epigenetic repression of cell cycle genes along with induction of interferon-related gene expression programs. These responses are separable, as the interferon gene expression program is mediated in a TBK1-dependent manner. Together, these data underscore the multifactorial impact of combination therapies acting through the RB pathway.Recent advancements in cancer immunotherapy have focused on tumor-associated macrophages (TAMs), which are linked to poor survival and pro-tumor functions in various cancers. Rather than eliminating this heterogeneous cell population from the tumor microenvironment, reprogramming and reinvigoration of these cells for improved immune surveillance and anti-tumor function have been discussed as the superior approach. Activation of the mannose receptor CD206 can reprogram these macrophages. Singh and colleagues have identified a novel therapeutic peptide, RP-182-PEG3-K(palmitic acid), binding that has improved stability, greater affinity to the CD206 receptor, and effectively increases phagocytosis, including cancer cell phagocytosis. RP-182-PEG3-K(palmitic acid)’s improved biophysical properties and effector signaling translated into enhanced tumor control, cooperated with immune checkpoint inhibition, and suggests that RP-182-PEG3-K(palmitic acid) is a candidate for future clinical applications.