Volume 3 Issue 7, July 2022

Though HER2 (ERBB2) exon 20 insertion mutations occur in ~2% of non-small-cell lung cancers, molecular targeted therapies for such cancers have been lacking. A study now identifies selective HER2 inhibitors that have marked efficacy against tumors driven by HER2 exon 20 insertions, without inhibiting wild-type EGFR activity.

Inhibition of XPO1-mediated nuclear export by selinexor represents a promising therapeutic strategy in acute myeloid leukemia. Because XPO1 is not specific for tumor-suppressive proteins, selinexor may also activate pro-oncogenic processes. A study now shows that inhibition of selinexor-induced, purinergic receptor–mediated AKT activation potentiates its anti-leukemic activity.

Despite the remarkable success of chimeric antigen receptor (CAR) T cell therapies in the treatment of hematological malignancies, this strategy remains challenging in solid tumors. One major obstacle is the hostile immunosuppressive tumor microenvironment. New research demonstrates that targeting PARP11 can overcome this immunosuppression and boost CAR T cell efficacy through stabilization of IFNAR1.

Lavie et al. review the recent advances in the field of cancer-associated fibroblasts, including their tissue-specific complexity and overall plasticity, as revealed by single-cell technologies.

Fuchs and colleagues delineate a mechanism by which PARP11-mediated IFNAR1 loss sustains an immunosuppressive tumor microenvironment and show that PARP11 inactivation can enhance chimeric antigen receptor T efficacy in preclinical solid tumor models.

Neumüller and colleagues identify and characterize potent HER2 exon 20 insertion-selective inhibitors with efficacy, which preserve wild-type epidermal growth factor receptor signaling in preclinical models of non-small cell lung cancer in vivo.

Wood and colleagues report that the XPO1 inhibitor selinexor activates PI3Ky-dependent AKT signaling in AML via upregulation of P2RY2 and demonstrate a synergistic effect of combining selinexor with inhibition of prosurvival AKT signaling.

Winter and colleagues demonstrate that metabolic adaptation to nutrient stress in the tumor microenvironment of pancreatic cancer leads to a dependency on IDH1, which is therapeutically actionable regardless of IDH1 mutation status.

Raj and colleagues show that ERX-41 inhibits lipase-independent functions of LIPA and induces ER stress in different tumor types, providing a therapeutic strategy in PDX models of pancreas, ovarian and triple-negative breast cancer.

Skokos and colleagues characterize human early-stage clear cell renal cell carcinoma with single-cell ATAC-seq and RNA-seq, identifying a spectrum of NFκB-promoted T cell dysfunction in the microenvironment and defining a pro-apoptotic signature.