A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance.

Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal cancer PDX models, resulting in striking increases in median survival. MTX-531 is exceptionally well tolerated in mice and uniquely does not lead to the hyperglycemia commonly seen with PI3K inhibitors. Here, we show that MTX-531 acts as a weak agonist of peroxisome proliferator-activated receptor-γ, an attribute that likely mitigates hyperglycemia induced by PI3K inhibition. This unique feature of MTX-531 confers a favorable therapeutic index not typically seen with PI3K inhibitors.

Loss of NF1 in Melanoma Confers Sensitivity to SYK Kinase Inhibition.

Neurofibromin 1 (NF1) loss of function (LoF) mutations are frequent in melanoma and drive hyperactivated RAS and tumor growth. NF1LoF melanoma cells, however, do not show consistent sensitivity to individual MEK, ERK, or PI3K/mTOR inhibitors. To identify more effective therapeutic strategies for treating NF1LoF melanoma, we performed a targeted kinase inhibitor screen. A tool compound named MTX-216 was highly effective in blocking NF1LoF melanoma growth in vitro and in vivo. Single-cell analysis indicated that drug-induced cytotoxicity was linked to effective cosuppression of proliferation marker Ki-67 and ribosomal protein S6 phosphorylation. The antitumor efficacy of MTX-216 was dependent on its ability to inhibit not only PI3K, its nominal target, but also SYK. MTX-216 suppressed expression of a group of genes that regulate mitochondrial electron transport chain and are associated with poor survival in patients with NF1LoF melanoma. Furthermore, combinations of inhibitors targeting either MEK or PI3K/mTOR with an independent SYK kinase inhibitor or SYK knockdown reduced the growth of NF1LoF melanoma cells. These studies provide a path to exploit SYK dependency to selectively target NF1LoF melanoma cells. SIGNIFICANCE: A kinase inhibitor screen identifies SYK as a targetable vulnerability in melanoma cells with NF1 loss of function.

Cyclooxygenase-2 Influences Response to Cotargeting of MEK and CDK4/6 in a Subpopulation of Pancreatic Cancers.

The ineffectiveness of chemotherapy in patients with pancreatic cancer highlights a critical unmet need in pancreatic cancer therapy. Two commonly mutated genes in pancreatic cancer, KRAS and CDKN2A, have an incidence exceeding 90%, supporting investigation of dual targeting of MEK and CDK4/6 as a potential therapeutic strategy for this patient population. An in vitro proliferation synergy screen was conducted to evaluate response of a panel of high passage and patient-derived pancreatic cancer models to the combination of trametinib and palbociclib to inhibit MEK and CDK4/6, respectively. Two adenosquamous carcinoma models, L3.6pl and UM59, stood out for their high synergy response. In vivo studies confirmed that this combination treatment approach was highly effective in subcutaneously implanted L3.6pl and UM59 tumor-bearing animals. Both models were refractory to single-agent treatment. Reverse-phase protein array analysis of L3.6pl tumors excised from treated animals revealed strong downregulation of COX-2 expression in response to combination treatment. Expression of COX-2 under a CMV-driven promoter and shRNA knockdown of COX-2 both led to resistance to combination treatment. Our findings suggest that COX-2 may be involved in the improved therapeutic outcome seen in some pancreatic tumors that fail to respond to MEK or CDK4/6 inhibitors alone but respond favorably to their combination.