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What is Acquired Resistance? and
How Does it Occur?
Gregory J. Riely@RielyMD
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Primary Resistance
Kwak EL, et al. NEJM 2010;363:1693-1703.
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Acquired Resistance
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Acquired Resistance
Kwak EL, et al. NEJM 2010;363:1693-1703.
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Crizotinib improves PFS compared to chemo
Shaw et al, NEJM 2013
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Definition of Acquired Resistance
Jackman et al JCO 2010
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How Does Drug Resistance Occur?
Holohan et al, Nature Reviews Cancer 2013
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How Does Drug Resistance Occur?
Holohan et al, Nature Reviews Cancer 2013
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Resistance Due to Altered Drug Distribution
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Overcoming Resistance Due to Altered Drug Distribution
Treated with Pulsatile Erlotinib 1500 mg weekly x 5 months
Grommes et al, Neuro Oncol 2011
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Resistance Due to Altered Drug Distribution
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Overcoming Resistance Due to Altered Drug Distribution
Weickhardt et al, JTO
Treated with “Locally Ablative Therapy”
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How Does Drug Resistance Occur?
Holohan et al, Nature Reviews Cancer 2013
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Natural Selection for Resistance
Drug Treatment
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Selection for Resistance in EGFR Mutant Lung Cancer
Riely G J et al. Clin Cancer Res 2006;12:7232-7241
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Erlotinib Bound to the EGFR Kinase Domain
Clark J, Cools J, Gilliland DG (2005) PLoS Med 2005
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Structural Models of EGFR Showing T790M
Clark J, Cools J, Gilliland DG (2005) PLoS Med 2005
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Natural Selection for Resistance
Drug Treatment
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Disease Flare
Riely et al Clin Cancer Res. 2007
Last day of TKI
Day 0
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Disease Flare
Riely et al Clin Cancer Res. 2007
Last day of TKI Off EGFR TKI
Day 0 Day 21
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Disease Flare
Riely et al Clin Cancer Res. 2007
Last day of TKI Off EGFR TKI Resumed TKI
Day 0 Day 21 Day 42
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How Does Drug Resistance Occur?
Holohan et al, Nature Reviews Cancer 2013
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Each site can develop resistance (or not) in its own way
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How Does Drug Resistance Occur?
Holohan et al, Nature Reviews Cancer 2013
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Conclusions
• Acquired Resistance is Different from Primary Resistance
• Resistance can happen in many ways• Targeting resistance depends on the type of
resistance that is observed