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      Patient-derived models of acquired resistance can identify effective drug combinations for cancer.

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          Abstract

          Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MAPK kinase (MEK) inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and fibroblast growth factor receptor (FGFR) inhibitors was active in an EGFR mutant resistant cancer with a mutation in FGFR3. Combined ALK and SRC (pp60c-src) inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.

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          First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations.

          Lecia V. Sequist, Renato G. Martins, David Spigel … (2008)
          Somatic mutations in the epidermal growth factor receptor (EGFR) correlate with increased response in patients with non-small-cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). The multicenter iTARGET trial prospectively examined first-line gefitinib in advanced NSCLC patients harboring EGFR mutations and explored the significance of EGFR mutation subtypes and TKI resistance mechanisms. Chemotherapy-naïve patients with advanced NSCLC with >or= 1 clinical characteristic associated with EGFR mutations underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21. Patients found to harbor any EGFR mutation were treated with gefitinib 250 mg/d until progression or unacceptable toxicity. The primary outcome was response rate. Ninety-eight patients underwent EGFR screening and mutations were detected in 34 (35%). EGFR mutations were primarily exon 19 deletions (53%) and L858R (26%) though 21% of mutation-positive cases had less common subtypes including exon 20 insertions, T790M/L858R, G719A, and L861Q. Thirty-one patients received gefitinib. The response rate was 55% (95% CI, 33 to 70) and median progression-free survival was 9.2 months (95% CI, 6.2 to 11.8). Therapy was well tolerated; 13% of patients had grade 3 toxicities including one grade 3 pneumonitis. Two patients with classic activating mutations exhibited de novo gefitinib resistance and had concurrent genetic anomalies usually associated with acquired TKI resistance, specifically the T790M EGFR mutation and MET amplification. First-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.
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            TSGene: a web resource for tumor suppressor genes

            Min Zhao, Jingchun Sun, Zhongming Zhao (2012)
            Tumor suppressor genes (TSGs) are guardian genes that play important roles in controlling cell proliferation processes such as cell-cycle checkpoints and inducing apoptosis. Identification of these genes and understanding their functions are critical for further investigation of tumorigenesis. So far, many studies have identified numerous TSGs and illustrated their functions in various types of tumors or normal samples. Furthermore, accumulating evidence has shown that non-coding RNAs can act as TSGs to prevent the tumorigenesis processes. Therefore, there is a growing demand to integrate TSGs with large-scale experimental evidence (e.g. gene expression and epigenetic signatures) to provide a comprehensive resource for further investigation of TSGs and their molecular mechanisms in cancer. To achieve this goal, we first developed a comprehensive literature-based database called TSGene (tumor suppressor gene database), freely available at http://bioinfo.mc.vanderbilt.edu/TSGene/. In the current release, TSGene contains 716 human (637 protein-coding and 79 non-coding genes), 628 mouse and 567 rat TSGs curated from UniProtKB, the Tumor Associated Gene database and 5795 PubMed abstracts. Additionally, the TSGene provides detailed annotations for each TSG, such as cancer mutations, gene expressions, methylation sites, TF regulations and protein–protein interactions.
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              Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK.

              Ryohei Katayama, Tahsin Khan, Cyril H Benes … (2011)
              The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion oncogene represents a molecular target in a small subset of non-small cell lung cancers (NSCLCs). This fusion leads to constitutive ALK activation with potent transforming activity. In a pivotal phase 1 clinical trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib (PF-02341066) demonstrated impressive antitumor activity in the majority of patients with NSCLC harboring ALK fusions. However, despite these remarkable initial responses, cancers eventually develop resistance to crizotinib, usually within 1 y, thereby limiting the potential clinical benefit. To determine how cancers acquire resistance to ALK inhibitors, we established a model of acquired resistance to crizotinib by exposing a highly sensitive EML4-ALK-positive NSCLC cell line to increasing doses of crizotinib until resistance emerged. We found that cells resistant to intermediate doses of crizotinib developed amplification of the EML4-ALK gene. Cells resistant to higher doses (1 μM) also developed a gatekeeper mutation, L1196M, within the kinase domain, rendering EML4-ALK insensitive to crizotinib. This gatekeeper mutation was readily detected using a unique and highly sensitive allele-specific PCR assay. Although crizotinib was ineffectual against EML4-ALK harboring the gatekeeper mutation, we observed that two structurally different ALK inhibitors, NVP-TAE684 and AP26113, were highly active against the resistant cancer cells in vitro and in vivo. Furthermore, these resistant cells remained highly sensitive to the Hsp90 inhibitor 17-AAG. Thus, we have developed a model of acquired resistance to ALK inhibitors and have shown that second-generation ALK TKIs or Hsp90 inhibitors are effective in treating crizotinib-resistant tumors harboring secondary gatekeeper mutations.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Science
                Title: Science (New York, N.Y.)
                ISSN (Electronic): 1095-9203
                ISSN (Print): 0036-8075
                Publication date (Electronic): Dec 19 2014
                Volume: 346
                Issue: 6216
                Affiliations
                [1 ] Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA.
                [2 ] Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology and Harvard Medical School, Boston, MA 02115, USA. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 136-791, South Korea.
                [3 ] Massachusetts General Hospital Cancer Center, Department of Pathology and Harvard Medical School, Boston, MA 02114, USA.
                [4 ] Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA. jengelman@partners.org cbenes@partners.org.
                Article
                Publisher Item ID: science.1254721 Mid ID: NIHMS659400
                DOI: 10.1126/science.1254721
                PubMed ID: 25394791
                SO-VID: a27c3e4f-f142-4599-9d55-acd2e0ad3e4f
                Copyright © Copyright © 2014, American Association for the Advancement of Science.
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