Karen E. Knudsen

Telemedicine has routinely been used in cancer care delivery for the past 3 years. The current state of digital health provides convenience and efficiency for both health-care professional and patient, but challenges exist in equitable access to virtual services. As increasingly newer technologies are added to telehealth platforms, it is essential to eliminate barriers to access through technical, procedural, and legislative improvements. Moving forward, implementation of new strategies can help eliminate disparities in virtual cancer care, facilitate delivery of treatment in the home, and improve real-time data collection for patient safety and clinical trial participation. The ultimate goal will be to extend high-quality survival for all patients with cancer through improved digital delivery of cancer care.

Gaps in the cancer care continuum are vast, both in the United States and globally. The American Cancer Society orchestrates an integrated, tripartite approach toward improving the lives of cancer patients and their families through research, advocacy, and patient support. With a focus on eradicating cancer disparities, the American Cancer Society aims to scale and deploy best practices worldwide through partnerships, to ensure everyone has an opportunity to prevent, detect, treat, and survive cancer.

Signaling rewiring allows tumors to survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate cancer unleashes eukaryotic initiation factor 3B (eIF3B)–dependent translation reprogramming of key mRNAs conferring resistance to androgen deprivation therapy (ADT) and promoting immune evasion. Mechanistically, MITF represses through direct promoter binding eIF3B, which in turn regulates the translation of specific mRNAs. Genome-wide eIF3B enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq) showed specialized binding to a UC-rich motif present in subsets of 5′ untranslated regions. Indeed, translation of the androgen receptor and major histocompatibility complex I (MHC-I) through this motif is sensitive to eIF3B amount. Notably, pharmacologic targeting of eIF3B-dependent translation in preclinical models sensitizes prostate cancer to ADT and anti–PD-1 therapy. These findings uncover a hidden connection between transcriptional and translational rewiring promoting therapy-refractory lethal prostate cancer and provide a druggable mechanism that may transcend into effective combined therapeutic strategies. Significance: Our study shows that specialized eIF3B-dependent translation of specific mRNAs released upon downregulation of the master transcription factor MITF confers castration resistance and immune evasion in lethal prostate cancer. Pharmacologic targeting of this mechanism delays castration resistance and increases immune-checkpoint efficacy. This article is featured in Selected Articles from This Issue, p. 2489

Supplemental Figure 1: PLX8394 does not alter CRAF or c-Src phosphorylation; Supplemental Figure 2. Treatment of xenograft-derived tumor pieces in an ex vivo explant system; Supplemental Figure 3: Patient sample extended data; Supplemental Figure 4: Parallel ex vivo dosing and homodimerization of vemurafenib and PLX8394 treatments; Supplemental Figure 5: PBRT characterization; Supplemental Figure 6: Targeting AKT and PDGFRβ in PBRT cell lines does not resensitize to PLX8394; Supplemental Figure 7: BRAF V600E splice variant analysis of PBRT cell lines and signaling and growth response of second-line therapies; Supplemental Methods.