In vivo genome-wide CRISPR screening identifies CITED2 as a driver of prostate cancer bone metastasis.

Most cancer deaths are due to metastatic dissemination to distant organs. Bone is the most frequently affected organ in metastatic prostate cancer and a major cause of prostate cancer deaths. Yet, our partial understanding of the molecular factors that drive bone metastasis has been a limiting factor for developing preventative and therapeutic strategies to improve patient survival and well-being. Although recent studies have uncovered molecular alterations that occur in prostate cancer metastasis, their functional relevance for bone metastasis is not well understood. Using genome-wide CRISPR activation and inhibition screens we have identified multiple drivers and suppressors of prostate cancer metastasis. Through functional validation, including an innovative organ-on-a-chip invasion platform for studying bone tropism, our study identifies the transcriptional modulator CITED2 as a novel driver of prostate cancer bone metastasis and uncovers multiple new potential molecular targets for bone metastatic disease.

Mechanisms of Acquired Resistance and Tolerance to EGFR Targeted Therapy in Non-Small Cell Lung Cancer.

Non-small cell lung cancers (NSCLC) harboring activating mutations of the epidermal growth factor receptor (EGFR) are treated with specific tyrosine kinase inhibitors (EGFR-TKIs) of this receptor, resulting in clinically responses that can generally last several months. Unfortunately, EGFR-targeted therapy also favors the emergence of drug tolerant or resistant cells, ultimately resulting in tumor relapse. Recently, cellular barcoding strategies have arisen as a powerful tool to investigate the clonal evolution of these subpopulations in response to anti-cancer drugs. In this review, we provide an overview of the currently available treatment options for NSCLC, focusing on EGFR targeted therapy, and discuss the common mechanisms of resistance to EGFR-TKIs. We also review the characteristics of drug-tolerant persister (DTP) cells and the mechanistic basis of drug tolerance in EGFR-mutant NSCLC. Lastly, we address how cellular barcoding can be applied to investigate the response and the behavior of DTP cells upon EGFR-TKI treatment.

Tolerant/Persister Cancer Cells and the Path to Resistance to Targeted Therapy.

The capacity of cancer to adapt to treatment and evolve is a major limitation for targeted therapies. While the role of new acquired mutations is well-established, recent findings indicate that resistance can also arise from subpopulations of tolerant/persister cells that survive in the presence of the treatment. Different processes contribute to the emergence of these cells, including pathway rebound through the release of negative feedback loops, transcriptional rewiring mediated by chromatin remodeling and autocrine/paracrine communication among tumor cells and within the tumor microenvironment. In this review, we discuss the non-genetic mechanisms that eventually result in cancer resistance to targeted therapies, with a special focus on those involving changes in gene expression.