Colorectal carcinoma side is associated with differences in key molecular features, some immediately druggable, with important prognostic effects which are maintained in metastatic lesions. Although within side significant molecular heterogeneity remains, our findings justify stratification of patients by side for retrospective and prospective analyses of drug efficacy and prognosis.

Graphical Abstract Highlights d PTPN11 inhibition is synthetic lethal with BRAF inhibitors in BRAF mutant colon cancer d PTPN11 inhibition blocks the effects of EGFR activation by BRAF inhibitors d PTPN11 inhibition is lethal to cancers with activated RTKs d Phosphorylation of PTPN11 is a biomarker of RTK-driven drug resistance in melanoma Correspondence r.bernards@nki.nl In Brief Using a synthetic lethality screen, Prahallad et al. report that PTPN11 suppression enhances the response to BRAF inhibition in BRAF mutant colon cancers by preventing the effects of receptor tyrosine kinase reactivation. These findings identify PTPN11 as a drug target to combat both intrinsic and acquired resistance to targeted cancer drugs. SUMMARY Most BRAF (V600E) mutant melanomas are sensitive to selective BRAF inhibitors, but BRAF mutant colon cancers are intrinsically resistant to these drugs because of feedback activation of EGFR. We performed an RNA-interference-based genetic screen in BRAF mutant colon cancer cells to search for phosphatases whose knockdown induces sensitivity to BRAF inhibition. We found that suppression of protein tyrosine phosphatase non-receptor type 11 (PTPN11) confers sensitivity to BRAF inhibitors in colon cancer. Mechanistically, we found that inhibition of PTPN11 blocks signaling from receptor tyro-sine kinases (RTKs) to the RAS-MEK-ERK pathway. PTPN11 suppression is lethal to cells that are driven by activated RTKs and prevents acquired resistance to targeted cancer drugs that results from RTK activation. Our findings identify PTPN11 as a drug target to combat both intrinsic and acquired resistance to several targeted cancer drugs. Moreover, activated PTPN11 can serve as a biomarker of drug resistance resulting from RTK activation.

COVID-19 pandemic challenges health system capacities in many countries. National healthcare services have to manage unexpected shortage of healthcare resources that have to be reallocated according to the principles of fair and ethical prioritisation, in order to maintain the highest levels of care to all patients, ensure the safety of patients and healthcare workers and save as many lives as possible. Beyond that, cancer care services have to pursue restructuring, following the same evidence-based dispositions. In this article, we propose guidance to the management of colorectal cancer during the pandemic, prioritised according to a three-tiered framework, based on expert clinical judgement and magnitude of benefit expected from specific interventions. Since the availability of resources for diagnostic procedures, surgery and postoperative care, systemic therapy and radiotherapy may differ, authors did separate prioritisation analyses. The impact of postponing or abrogating cancer interventions on outcomes according to a high, medium or low priority scale, is outlined and discussed. The implementation of healthcare services using telemedicine is explored: it reveals itself as functional and effective for limiting patients’ need to travel to centres and thereby has the potential to reduce diffusion of severe acute respiratory syndrome coronavirus 2. Colorectal cancer demands a considerable amount of medical resources. Therefore, the redefinition of its diagnostic and therapeutic algorithms with a rigorous method is crucial in order to ensure the highest quality of continuum of care in the broader context of the pandemic and the challenged healthcare systems.

Purpose: Cancer cell survival, invasion, and metastasis depend on cancer cell proliferation and on tumorinduced angiogenesis. We evaluated the efficacy of the combination of sorafenib and erlotinib or cetuximab.Experimental Design: Sorafenib, erlotinib, and cetuximab, alone or in combination, were tested in vitro in a panel of non-small cell lung cancer (NSCLC) and colorectal cancer cell lines and in vivo in H1299 tumor xenografts.Results: Epidermal growth factor receptor (EGFR) ligand mRNAs were expressed in all NSCLC and colorectal cancer cell lines with variable levels ranging from 0.4-to 8