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Cancer cells often co-opt post-transcriptional regulatory mechanisms to achieve pathologic expression of gene networks that drive metastasis. Translational control is a major regulatory hub in oncogenesis; however, its effects on cancer progression remain poorly understood. Here, to address this, we used ribosome profiling to compare genome-wide translation efficiencies of poorly and highly metastatic breast cancer cells and patient-derived xenografts. We developed dedicated regression-based methods to analyse ribosome profiling and alternative polyadenylation data, and identified heterogeneous nuclear ribonucleoprotein C (HNRNPC) as a translational controller of a specific mRNA regulon. We found that HNRNPC is downregulated in highly metastatic cells, which causes HNRNPC-bound mRNAs to undergo 3′ untranslated region lengthening and, subsequently, translational repression. We showed that modulating HNRNPC expression impacts the metastatic capacity of breast cancer cells in xenograft mouse models. In addition, the reduced expression of HNRNPC and its regulon is associated with the worse prognosis in breast cancer patient cohorts.

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non–small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%–63%) with median duration of response of 14 months (5.0–not reached) and median progression-free survival of 7.3 months (4.4–15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors.Significance:No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601

Background Suspension of cancer screening and treatment programs were instituted to preserve medical resources and protect vulnerable populations. This research aims to investigate the implications of COVID-19 on cancer management and clinical outcomes for patients with prostate and colorectal cancer in Canada. Methods We examined hospital cancer screening, diagnosis, treatment, length of stay, and mortality data among prostate and colorectal cancer patients between April 2017 and March 2021. Baseline trends were established with data between April 2017 and March 2020 for comparison with data collected between April 2020 and March 2021. Scenario analyses were performed to assess the incremental capacity requirements needed to restore hospital cancer care capacities to the pre-pandemic levels. Results For prostate cancer, A 12% decrease in diagnoses and 5.3% decrease in treatment activities were observed during COVID-19 between April 2020 and March 2021. Similarly, a 43% reduction in colonoscopies, 11% decrease in diagnoses and 10% decrease in treatment activities were observed for colorectal cancers. An estimated 1,438 prostate and 2,494 colorectal cancer cases were undiagnosed, resulting in a total of 620 and 1,487 unperformed treatment activities for prostate and colorectal cancers, respectively, across nine provinces in Canada. To clear the backlogs of unperformed treatment procedures will require an estimated 3%-6% monthly capacity increase over the next 6 months. Interpretation. A concerted effort from all stakeholders is required to immediately ameliorate the backlogs of cancer detection and treatment activities. Mitigation measures should be implemented to minimize future interruptions to cancer care in Canada.