What is Acquired Resistance? and How Does it Occur? Gregory J.

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Presentation transcript:

What is Acquired Resistance? and How Does it Occur? Gregory J.

Primary Resistance Kwak EL, et al. NEJM 2010;363:

Acquired Resistance

Kwak EL, et al. NEJM 2010;363:

Crizotinib improves PFS compared to chemo Shaw et al, NEJM 2013

Definition of Acquired Resistance Jackman et al JCO 2010

How Does Drug Resistance Occur? Holohan et al, Nature Reviews Cancer 2013

How Does Drug Resistance Occur? Holohan et al, Nature Reviews Cancer 2013

Resistance Due to Altered Drug Distribution

Overcoming Resistance Due to Altered Drug Distribution Treated with Pulsatile Erlotinib 1500 mg weekly x 5 months Grommes et al, Neuro Oncol 2011

Resistance Due to Altered Drug Distribution

Overcoming Resistance Due to Altered Drug Distribution Weickhardt et al, JTO Treated with “Locally Ablative Therapy”

How Does Drug Resistance Occur? Holohan et al, Nature Reviews Cancer 2013

Natural Selection for Resistance Drug Treatment

Selection for Resistance in EGFR Mutant Lung Cancer Riely G J et al. Clin Cancer Res 2006;12:

Erlotinib Bound to the EGFR Kinase Domain Clark J, Cools J, Gilliland DG (2005) PLoS Med 2005

Structural Models of EGFR Showing T790M Clark J, Cools J, Gilliland DG (2005) PLoS Med 2005

Natural Selection for Resistance Drug Treatment

Disease Flare Riely et al Clin Cancer Res Last day of TKI Day 0

Disease Flare Riely et al Clin Cancer Res Last day of TKIOff EGFR TKI Day 0Day 21

Disease Flare Riely et al Clin Cancer Res Last day of TKIOff EGFR TKIResumed TKI Day 0Day 21Day 42

How Does Drug Resistance Occur? Holohan et al, Nature Reviews Cancer 2013

Each site can develop resistance (or not) in its own way

How Does Drug Resistance Occur? Holohan et al, Nature Reviews Cancer 2013

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