Discovery of novel furanylbenzamide inhibitors that target oncogenic tyrosine phosphatase SHP2 in leukemia cells.

Disturbance of the dynamic balance between tyrosine phosphorylation and dephosphorylation of signaling molecules, controlled by protein tyrosine kinases and protein tyrosine phosphatases (PTPs), is known to lead to the development of cancer. While most approved targeted cancer therapies are tyrosine kinase inhibitors, PTPs have long been stigmatized as undruggable and have only recently gained renewed attention in drug discovery. One PTP target is the Src-homology 2 domain-containing phosphatase 2 (SHP2). SHP2 is implicated in tumor initiation, progression, metastasis, and treatment resistance, primarily because of its role as a signaling nexus of the extracellular signal-regulated kinase pathway, acting upstream of the small GTPase Ras. Efforts to develop small molecules that target SHP2 are ongoing, and several SHP2 allosteric inhibitors are currently in clinical trials for the treatment of solid tumors. However, while the reported allosteric inhibitors are highly effective against cells expressing WT SHP2, none have significant activity against the most frequent oncogenic SHP2 variants that drive leukemogenesis in several juvenile and acute leukemias. Here, we report the discovery of novel furanylbenzamide molecules as inhibitors of both WT and oncogenic SHP2. Importantly, these inhibitors readily cross cell membranes, bind and inhibit SHP2 under physiological conditions, and effectively decrease the growth of cancer cells, including triple-negative breast cancer cells, acute myeloid leukemia cells expressing either WT or oncogenic SHP2, and patient-derived acute myeloid leukemia cells. These novel compounds are effective chemical probes of active SHP2 and may serve as starting points for therapeutics targeting WT or mutant SHP2 in cancer.

Absence of HIF1A Leads to Glycogen Accumulation and an Inflammatory Response That Enables Pancreatic Tumor Growth.

Cancer cells respond to hypoxia by upregulating the hypoxia-inducible factor 1α (HIF1A) transcription factor, which drives survival mechanisms that include metabolic adaptation and induction of angiogenesis by VEGF. Pancreatic tumors are poorly vascularized and severely hypoxic. To study the angiogenic role of HIF1A, and specifically probe whether tumors are able to use alternative pathways in its absence, we created a xenograft mouse tumor model of pancreatic cancer lacking HIF1A. After an initial delay of about 30 days, the HIF1A-deficient tumors grew as rapidly as the wild-type tumors and had similar vascularization. These changes were maintained in subsequent passages of tumor xenografts in vivo and in cell lines ex vivo. There were many cancer cells with a "clear-cell" phenotype in the HIF1A-deficient tumors; this was the result of accumulation of glycogen. Single-cell RNA sequencing (scRNA-seq) of the tumors identified hypoxic cancer cells with inhibited glycogen breakdown, which promoted glycogen accumulation and the secretion of inflammatory cytokines, including interleukins 1ß (IL1B) and 8 (IL8). scRNA-seq of the mouse tumor stroma showed enrichment of two subsets of myeloid dendritic cells (cDC), cDC1 and cDC2, that secreted proangiogenic cytokines. These results suggest that glycogen accumulation associated with a clear-cell phenotype in hypoxic cancer cells lacking HIF1A can initiate an alternate pathway of cytokine and DC-driven angiogenesis. Inhibiting glycogen accumulation may provide a treatment for cancers with the clear-cell phenotype. SIGNIFICANCE: These findings establish a novel mechanism by which tumors support angiogenesis in an HIF1α-independent manner.