Selected Articles from This Issue

EGFR-mutant lung cancers can acquire RET fusion-mediated bypass resistance to osimertinib. Rotow and colleagues present the largest series of patients with these cancers who were prospectively treated in a multicenter cohort with the combination of EGFR and RET kinase inhibitor therapy (osimertinib and selpercatinib). The majority of patients benefitted from treatment with a response rate of 50%, a disease control rate of 83%, and a median treatment of duration 7.9 months, highlighting the potential use of the combination in clinic. On-target (second site EGFR or RET kinase domain mutations), off-target (ALK fusion, KRAS/BRAF mutation), and polyclonal resistance were observed. The authors propose that further treatment relapse can be mediated by competing clones harboring steric hindrance to EGFR/RET kinase engagement or non-EGFR/RET-mediated MAPK pathway reactivation.

Low overall survival (OS) rates in post-treatment glioblastoma (GBM) patients highlight a need for new treatment options. Enrichment of immunosuppressive, extracellular-facing phosphatidylserine (PS) in GBM makes PS an attractive therapeutic candidate. In a phase II clinical trial, Ly and colleagues found that the addition of bivatuximab, which reverses P2-mediated immunosuppression, to standard radiation and temozolomide treatment in newly diagnosed GMB patients increased OS rates, with 73% of patients surviving longer than 12 months. This study is the first to demonstrate the on-target effects of bivatuximab in patients, showing a post-treatment reduction in immunosuppressive-related myeloid-derived suppressor cells and macrophages. Additionally, the authors found that elevated expression of myeloid-related genes in pretreated tumor tissue was associated with longer PFS and OS rates, suggesting myeloid transcript levels may be a potential indicator of bivatuximab treatment response.

Pancreatic ductal adenocarcinoma is associated with poor treatment outcomes, and identifying broadly effective treatments is hindered by an immunosuppressive tumor microenvironment. Activation of the stimulator of interferon genes (STING) pathway is linked to tumor-cell cytotoxicity and elevated levels of STING in pancreatic tumors and make it a potential therapeutic target. Phase I clinical trials have shown promising results using the STING agonist diABZI; however, combination therapies are needed to increase efficacy. Ghukasyan and colleagues screened 430 kinase inhibitors in combination with diABZI and found that MEK inhibitors displayed the highest synergistic effects on tumor-cell death, particularly in cells with high STING expression. Furthermore, the authors demonstrated that MEK inhibition suppresses NF-κb activation, mediating STING-dependent Type I interferon production and inducing in vitro cell death and in vivo tumor regression. The authors highlight the synergistic enhancement of STING agonist-mediated cytotoxicity through MEK inhibition and note that a biomarker-guided approach may help select patients and maximize the benefits of STING-driven tumor cell cytotoxicity.

Patients with relapsed T-acute lymphoblastic leukemia (T-ALL) have poor survival outcomes and limited available treatment options. The balance between cell survival and cell death is disrupted in blood cancer cells when prosurvival BCL-2 proteins sequester cell death effector proteins, and although BH3 mimetics—which bind to BCL-2 and restore apoptosis—have shown activity in certain hematological cancers, the development of BH3 resistance is a significant challenge. With the goal of developing effective combination therapies, Saygin and colleagues investigated BH3 resistance mechanisms and identified the tyrosine kinase inhibitor-targetable LCK and ACK1 signaling pathways as drivers of BH3 resistance. The authors showed that NWP-0476, a novel BCL-2/BCL-xL dual inhibitor, was effective against T-ALL and that the combination of NWP-0476 and the tyrosine kinase inhibitor dasatinib acted synergistically. The authors highlight the clinical applications of this study, which has set the stage for an early clinical study investigating BH3 memetic/TKI combination therapy that is currently underway.