Volume 5, Issue 1, Pages 11-29 (January 2019) A Road Map to Personalizing Targeted Cancer Therapies Using Synthetic Lethality  Sreejit Parameswaran, Deeksha Kundapur, Frederick S. Vizeacoumar, Andrew Freywald, Maruti Uppalapati, Franco J. Vizeacoumar  Trends in Cancer  Volume 5, Issue 1, Pages 11-29 (January 2019) DOI: 10.1016/j.trecan.2018.11.001 Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 1 Are Current Strategies for Developing Targeted Therapy Good Enough? (A) Current targeted therapies focus on specific genetic alterations without considering the adaptive potential of tumor cells and genetic diversity of patients often leading to failure of promising drugs in clinical trials. (B) Concept of SL where targeting Gene A (red – normally nonlethal) after assessing levels of a biomarker Gene B (purple), induces tumor cell-specific death. (C) Personalized targeted therapeutics using SL approach in a genome profiled patient cohort. The treatment inhibits Gene A (red), which is normally expressed and nonlethal, when the loss of Gene B (purple) can be used as a biomarker. Abbreviations: LOF, loss of function; SL, synthetic lethality. Trends in Cancer 2019 5, 11-29DOI: (10.1016/j.trecan.2018.11.001) Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 2 How to Overcome Tumor Heterogeneity and the Limitations of the Synthetic Lethal Approach. (A) Strategies that may eliminate heterogeneous cell populations are represented. Targeting a single driver alone is not sufficient to eradicate heterogeneous cell populations. While multitarget inhibition may reduce tumor burden to some extent, it may not be a fruitful approach. SL/SDL approaches that can take advantage of genes that regulate chromosomal instability, or a major cytogenetic aberration, may be among the best approaches. However, it remains to be seen if cancer stem cells will be susceptible to this approach. (B) Two different approaches that may effectively be used to overcome the deficiencies of the synthetic lethal approach. Abbreviations: A, BRCA gene; B, PARP inhibitor; C, EGFR/IGF-1R/VEGFR/HSP90/CHK inhibitors; SDL, synthetic dosage lethality; SL, synthetic lethality; X, HDAC inhibitor. Trends in Cancer 2019 5, 11-29DOI: (10.1016/j.trecan.2018.11.001) Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 3 Protein-Based Inhibitors Function as Effective Targeting Mechanism. PPIs are the basis for various cellular functions. Unlike gene knockdown, protein-based inhibitors can physically disrupt specific PPIs, without affecting other essential functions, to reduce potential toxicity of disrupting essential functions. Abbreviations: PPI, protein–protein interaction. Trends in Cancer 2019 5, 11-29DOI: (10.1016/j.trecan.2018.11.001) Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 4 Road Map to Effective Cancer Treatment Strategies. (A) Flowchart demonstrating the current strategies in targeted therapy approach and the additional steps to be carried out for personalized targeted therapy. (B) A road map summarizing the roles of synthetic lethality/synthetic dosage lethality strategies in advancing drug development pipelines. Trends in Cancer 2019 5, 11-29DOI: (10.1016/j.trecan.2018.11.001) Copyright © 2018 Elsevier Inc. Terms and Conditions