Highlights from Recent Cancer Literature

Abstract

APC-mutant colorectal cancers are dependent on mTORC1 to promote protein translation, sensitizing them to rapalogs. Similar efficacy of rapalogs is not observed in KRAS-mutant colorectal cancer. Knight and colleagues showed that protein translation is altered in APC;KRAS-mutant cells compared with APC-mutant cells, with translation initiation combining with translation elongation to drive cell proliferation. This dependence on rewired translation underlies the functional uncoupling of protein synthesis inhibition and attenuation of proliferation by rapamycin in APC;KRAS tissue. This enhanced translation initiation was regulated by the MAP kinase-interacting kinase (MNK)/eIF4E axis, which drove a specific set of proproliferative mRNAs that included MYC. Disruption of MNK/eIF4E was insufficient to suppress APC;KRAS-driven tumorigenesis unless done in combination with rapamycin, as both translational mechanisms regulated levels of MYC in concert.Expert Commentary: A therapeutic strategy to target KRAS-mutant colorectal cancer was described, along with a companion diagnostic to identify those patients likely to benefit.Knight JRP, Alexandrou C, Skalka GL, Vlahov N, Pennel K, Officer L, et al. MNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression. Cancer Discov 2021;11:1228–47.Ras proteins are frequently mutated in cancer. Recent advances have been made in developing allele-specific inhibitors to target mutant KrasG12C, including sotorasib (AMG 510), which recently received accelerated FDA approval. As a broad strategy to inhibit oncogenic Ras proteins, Nomura and colleagues generated a ubiquitin-like Ras-binding domain (RBD) compound specific for Ras in the nanomolar range. They identified Pen-cRaf-v1 upon screening of 51 combinations of RBD and cell-penetrating peptides. This peptide targeted Ras proteins carrying both G12C and non-G12C mutations. The cell-permeable Pen-cRaf-v1 peptide inhibited Ras binding to interacting proteins, which enabled targeting of cancer cell lines with KRAS mutations. Importantly, Pen-cRaf-v1 showed similar efficiency as BI-2852, a well-known pan-Ras inhibitor, and it demonstrated strong target specificity. The identified peptide can be used as scaffold for development of even better Ras inhibitors.Expert Commentary: This study suggests that cell-permeable peptides can be used as lead compounds for targeting oncogenic Ras and for possible drug development for treating Ras-driven human cancer.Nomura TK, Heishima K, Sugito N, Sugawara R, Ueda H, Yukihiro A, et al. Specific inhibition of oncogenic RAS using cell-permeable RAS-binding domains. Cell Chemical Biology; Published online May 4, 2021; DOI: 10.1016/j.chembiol.2021.04.013.Drugs targeting the MDM2-p53 tumor suppressive axis can potently stimulate antitumor cytotoxic T cells. Zhou and colleagues deleted MDM2 in T cells, demonstrating that MDM2 controlled tumor growth by supporting the survival and function of tumor-infiltrating CD8+ T cells. STAT5 is the major STAT activated downstream of IL2, an immune-boosting cytokine. MDM2 stabilized STAT5 in T cells by forming a complex with the ubiquitin-ligase c-Cbl, inhibiting its capacity to ubiquitinate and degrade STAT5. This promoted survival and proliferation of CD8+ T cells. In patients, an MDM2 high gene signature correlated with reduced apoptosis and an increased IFNγ signature in tumor-infiltrating T cells. Importantly, APG-115, a drug that blocks MDM2-p53 interactions, increased MDM2 levels in T cells and boosted antitumor immunity in p53-mutant tumor-bearing mice.Expert Commentary: Blocking interactions between MDM2 and p53 could be used therapeutically to (i) boost p53 activity in tumors with functional p53 and (ii) elevate levels of MDM2 in tumor-infiltrating T cells, increasing their survival and function against cancers.Zhou J, Kryczek I, Li S, Li X, Aguilar A, Wei S, et al. The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated antitumor immunity. Nat Immunol 2021;22:460–70.Durno and colleagues subjected a prospective cohort of 89 children and young adults with constitutional mismatch repair deficiency syndrome (cMMRD) to surveillance with brain and whole-body MRI, upper and lower gastrointestinal tract endoscopy, abdominal ultrasound, and complete blood count. Of 139 tumors detected in a prospective cohort, 28% were detected through surveillance at the asymptomatic stage. The remainder presented with symptoms. Not surprisingly, survival was dramatically improved for those patients with asymptomatic tumors. When dividing the cohort into full surveillance, partial surveillance, and no surveillance, overall survival was significantly prolonged for the surveillance group. Benign tumors, specifically low-grade gliomas, all underwent malignant transformation within 2 years, supporting early resective surgery.Expert Commentary: The observation that immune checkpoint inhibition is highly effective in hypermutant cancers, particularly in the setting of cMMRD, has provided dramatic improvement in survival for previously uncurable cancers. This study provides proof of principle for aggressive and uniform surveillance in children with cMMRD and may open the door to early therapeutic intervention though immunotherapy and/or surgery.Durno C, Ercan AB, Bianchi V, Edwards M, Aronson M, Galati M, et al. Survival benefit for individuals with constitutional mismatch repair deficiency undergoing surveillance. Journal of Clinical Oncology; Published online May 4, 2021; DOI: 10.1200/jco.20.02636.Current small molecules cannot inhibit CDK12 selectively over CDK13 because of nearly identical structures. Jiang and colleagues used computational modeling to demonstrate that CDK12 can be selectively targeted and, after optimization using in vitro and cell-based assays, identified BSJ-4-116 as a CDK12-selective bifunctional degrader. This class of therapeutics utilizes two targeting moieties connected by a linker to selectively degrade a protein of interest. To validate preclinical utility, the authors showed that BSJ-4-116 phenocopied other CDK12 inhibitors, downregulating DNA damage response genes and synergizing with PARP inhibitors. Finally, the authors demonstrated that acquired resistance to BSJ-4-116 occurred through point mutations in CDK12.Expert Commentary: This report describes the first selective CDK12 degrader molecule and further validates the contribution of CDK12 to the phenomenon of premature termination and polyadenylation of long genes. This paper also demonstrates resistance acquired through mutations that disrupt ternary complex formation with the E3 ligase. This information may be useful to clinicians for future stratification of patients into inhibitor versus degrader treatment protocols.Jiang B, Gao Y, Che J, Lu W, Kaltheuner IH, Dries R, et al. Discovery and resistance mechanism of a selective CDK12 degrader. Nat Chem Biol. 2021;17:675–83.Expression of DEAD-box RNA helicase 3X (DDX3X) is increased in primary and metastatic breast cancer. As high expression of DDX3X correlates with reduced patient survival, DDX3X is a potential therapeutic target in breast cancer. Choi and colleagues found that knockdown or inhibition of DDX3X resulted in cytoplasmic accumulation of double-stranded RNAs (dsRNA) in breast cancer cells, which activated the MDA5-mediated dsRNA sensing pathway to stimulate production of type I IFN. DDX3X interacted with ADAR1 to promote ADAR1-mediated A-to-I dsRNA editing. Depletion of both DDX3X and ADAR1 synergistically activated the cytosolic dsRNA pathway in breast cancer cells. DDX3X deficiency in mouse mammary tumors enhanced antitumor immunity by activating tumor-intrinsic IFN signaling, increasing antigen presentation, and promoting cytotoxic T and dendritic cell tumor infiltration.Expert Commentary: This study elucidates the novel role of DDX3X in regulating endogenous cellular dsRNA homeostasis and type I IFN signaling in breast cancer and suggests targeting DDX3X in combination with immune checkpoint blockade as a novel therapy.Choi H, Kwon J, Cho MS, Sun Y, Zheng X, Wang J, et al. Targeting DDX3X triggers antitumor immunity via a dsRNA-mediated tumor-intrinsic type I interferon response. Cancer Res 2021;81:3607–20.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.