TY - JOUR
T1 - Differential sensitivity analysis for resistant malignancies (DISARM) identifies common candidate therapies across platinum-resistant cancers
AU - Gay, Carl M.
AU - Tong, Pan
AU - Cardnell, Robert J.
AU - Sen, Triparna
AU - Su, Xiao
AU - Ma, Jun
AU - Bara, Rasha O.
AU - Johnson, Faye M.
AU - Wakefield, Chris
AU - Heymach, John V.
AU - Wang, Jing
AU - Byers, Lauren A.
N1 - Funding Information:
This work was supported by NIH/NCI T32 CA-009666 (C.M. Gay), the Conquer Cancer Foundation of ASCO/Lung Cancer Alliance Young Investigator Award (C.M. Gay), NIH/NCI 1-R01-CA207295 (L.A. Byers), the MDACC CCSG (P30CA016672), the LUNGevity Foundation (L.A. Byers), the MD Anderson Physician Scientist Award (L.A. Byers), Rexanna's Foundation for Fighting Lung Cancer (L.A. Byers and J.V. Heymach), the David Bruton Jr. Chairmanship in Cancer Research (J.V. Heymach), The Sheikh Khalifa Bin Zayed Al Nahyan Institute for the Personalized Cancer Therapy's (IPCT's) Center for Professional Education and Training (L.A. Byers), and by generous philanthropic contributions to The University of Texas MD Anderson Moon Shots Program (L.A. Byers, J. Wang, J.V. Heymach).
Funding Information:
This work was supported by NIH/NCI T32 CA-009666 (C.M. Gay), the Conquer Cancer Foundation of ASCO/Lung Cancer Alliance Young Investigator Award (C.M. Gay), NIH/NCI 1-R01-CA207295 (L.A. Byers), the MDACC CCSG (P30CA016672), the LUNGevity Foundation (L.A. Byers), the MD Anderson Physician Scientist Award (L.A. Byers), Rexanna's Foundation for Fighting Lung Cancer (L.A. Byers and J.V. Heymach), the David Bruton Jr. Chairmanship in Cancer Research (J.V. Heymach), The Sheikh Khalifa Bin Zayed Al Nahyan Institute for the Personalized Cancer Therapy's (IPCT's) Center for Professional Education and Training (L.A. Byers), and by generous philanthropic contribu-
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Purpose: Despite a growing arsenal of approved drugs, therapeutic resistance remains a formidable and, often, insurmountable challenge in cancer treatment. The mechanisms underlying therapeutic resistance remain largely unresolved and, thus, examples of effective combinatorial or sequential strategies to combat resistance are rare. Here, we present Differential Sensitivity Analysis for Resistant Malignancies (DISARM), a novel, integrated drug screen analysis tool designed to address this dilemma. Experimental Design: DISARM, a software package and web-based application, analyzes drug response data to prioritize candidate therapies for models with resistance to a reference drug and to assess whether response to a reference drug can be utilized to predict future response to other agents. Using cisplatin as our reference drug, we applied DISARM to models from nine cancers commonly treated with first-line platinum chemotherapy including recalcitrant malignancies such as small cell lung cancer (SCLC) and pancreatic adenocarcinoma (PAAD). Results: In cisplatin-resistant models, DISARM identified novel candidates including multiple inhibitors of PI3K, MEK, and BCL-2, among other classes, across unrelated malignancies. Additionally, DISARM facilitated the selection of predictive biomarkers of response and identification of unique molecular subtypes, such as contrasting ASCL1-low/cMYC-high SCLC targetable by AURKA inhibitors and ASCL1-high/cMYC-low SCLC targetable by BCL-2 inhibitors. Utilizing these predictions, we assessed several of DISARM's top candidates, including inhibitors of AURKA, BCL-2, and HSP90, to confirm their activity in cisplatin-resistant SCLC models. Conclusions: DISARM represents the first validated tool to analyze large-scale in vitro drug response data to statistically optimize candidate drug and biomarker selection aimed at overcoming candidate drug resistance.
AB - Purpose: Despite a growing arsenal of approved drugs, therapeutic resistance remains a formidable and, often, insurmountable challenge in cancer treatment. The mechanisms underlying therapeutic resistance remain largely unresolved and, thus, examples of effective combinatorial or sequential strategies to combat resistance are rare. Here, we present Differential Sensitivity Analysis for Resistant Malignancies (DISARM), a novel, integrated drug screen analysis tool designed to address this dilemma. Experimental Design: DISARM, a software package and web-based application, analyzes drug response data to prioritize candidate therapies for models with resistance to a reference drug and to assess whether response to a reference drug can be utilized to predict future response to other agents. Using cisplatin as our reference drug, we applied DISARM to models from nine cancers commonly treated with first-line platinum chemotherapy including recalcitrant malignancies such as small cell lung cancer (SCLC) and pancreatic adenocarcinoma (PAAD). Results: In cisplatin-resistant models, DISARM identified novel candidates including multiple inhibitors of PI3K, MEK, and BCL-2, among other classes, across unrelated malignancies. Additionally, DISARM facilitated the selection of predictive biomarkers of response and identification of unique molecular subtypes, such as contrasting ASCL1-low/cMYC-high SCLC targetable by AURKA inhibitors and ASCL1-high/cMYC-low SCLC targetable by BCL-2 inhibitors. Utilizing these predictions, we assessed several of DISARM's top candidates, including inhibitors of AURKA, BCL-2, and HSP90, to confirm their activity in cisplatin-resistant SCLC models. Conclusions: DISARM represents the first validated tool to analyze large-scale in vitro drug response data to statistically optimize candidate drug and biomarker selection aimed at overcoming candidate drug resistance.
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U2 - 10.1158/1078-0432.CCR-18-1129
DO - 10.1158/1078-0432.CCR-18-1129
M3 - Article
C2 - 30257981
AN - SCOPUS:85059466366
SN - 1078-0432
VL - 25
SP - 346
EP - 357
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -