Selected Articles from This Issue

Alterations to androgen receptor transcript processing in response to hormone therapy culminates in the formation of androgen receptor splice variants (AR-V) in advanced prostate cancer. They are principally generated by aberrant splicing and exhibit constitutive oncogenic signaling that is refractory to the current repertoire of approved therapeutics for prostate cancer treatment. As such, defining treatment modalities to inactivate their function represents an important clinical need. Critically, our understanding of how AR-Vs are synthesized by cellular machinery remains a key knowledge gap which could furnish the field with new therapeutic targets. In this article, Walker and colleagues applied an unbiased CRISPR/Cas9 screen, individually targeting all splicing regulators, to comprehensively define the splicing requirements for the synthesis of AR-Vs in prostate cancer. From the screen, CWC22 and MFAP1 were identified to be important regulators of AR-Vs in multiple models of disease in which their depletion reduced AR-V synthesis, downstream transcriptional signaling, and cell proliferation. Ultimately, therapeutically targeting MFAP1 and CWC22 could expedite more effective treatments in the advanced disease setting.Overcoming therapy resistance and leveraging immunotherapies remain substantial challenges in managing tubo-ovarian high-grade serous carcinoma (HGSC). Epigenomic remodeling by the epigenetic writers euchromatic histone lysine N-methyltransferases 1 and 2 (EHMT1/2) promotes therapy resistance. In this study, Nguyen and colleagues used a unique, poly(ADP-ribose) polymerase (PARP) inhibitor-resistant HGSC mouse model to explore how targeting EHMT1/2 alters the tumor epigenome and triggers an immune response mimicking viral infection. The authors found that PARP inhibitor-resistant tumors had higher levels of immune-suppressive T regulatory cells. Blocking EHMT1/2 enhanced response to PARP inhibitor olaparib by reducing cancer cell viability. Combining EHMT1/2 and PARP inhibition increased interferon signaling and abundances of immune-stimulating cytokines (CCL5, CXCL10, and CXCL11). Mechanistically, the combination upregulates transposable element expression and induces the accumulation of immune-stimulating, cytosolic, double-stranded RNA. Combination therapy with EHMT1/2 inhibitor (EZM8266) and olaparib decreased tumor size, increased CCL5 levels, and reduced tumor-specific EHMT1/2-mediated histone H3 lysine 9 dimethylation (H3K9Me2). Importantly, this anti-tumor effect depended on the presence of CD8+ T cells. Overall, the study suggests that targeting EHMT1/2 could overcome resistance in HGSC while enhancing anti-tumor immunity.Patients with V600EBRAF-mutant (MT) colorectal cancer have poor prognosis and limited response to therapies. There is a need to further underpin the aggressive tumor biology of V600EBRAFMT colorectal cancer. In their study, Griffin and colleagues performed differential gene expression analyses between BRAF-wild-type and MT colorectal cancer cells, identifying significant enrichment of unfolded protein response (UPR) and DNA repair pathways in V600EBRAFMT colorectal cancer. Using a molecularly characterized colorectal cancer cell line panel, the authors found that oncogenic BRAF mediates sensitivity to the UPR activator BOLD-100. Using a systems biology approach, the authors demonstrated BOLD-100 treatment induced V600EBRAFMT-dependent reactive oxygen species generation, enhancing replication stress and activation of the ATR/CHK1 pathway—a key mediator of resistance to BOLD-100. Further analysis demonstrated that this resistance mechanism involves the aryl hydrocarbon receptor transcription factor and CYP1A1. Importantly, pharmacological inhibition of ATR synergistically enhanced BOLD-100-induced apoptosis and growth inhibition in V600EBRAFMT colorectal cancer models. Overall, this study underscores the critical role of ATR-mediated replication stress response in V600EBRAFMT colorectal cancer and combining BOLD-100 with ATR inhibitors represents a novel therapeutic strategy for this clinically aggressive colorectal cancer subtype.