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Published on: July 21, 2018
A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response
Zhao Chen1, Katherine Cheng, Zandra Walton
1Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.
Insights
Co-clinical trials reveal that MEK inhibitor selumetinib benefits KRAS-mutant lung cancers with p53 loss but not LKB1 loss. Genetic biomarkers predict response to combination therapy.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Lung cancer treatment is often based on single oncogenic drivers, but responses vary significantly.
- The impact of co-occurring mutations, particularly tumor suppressor loss, on targeted therapy efficacy is poorly understood.
- KRAS-mutant lung cancers represent a significant patient population with unmet therapeutic needs.
Purpose of the Study:
- To investigate the efficacy of combining MEK inhibitor selumetinib with docetaxel in KRAS-mutant lung cancer models.
- To explore the role of tumor suppressor loss (p53 and LKB1) in mediating response or resistance to this combination therapy.
- To identify predictive biomarkers for differential treatment responses using co-clinical trials.
Main Methods:
- Utilized genetically engineered mouse models for a co-clinical trial mirroring human studies.
- Assessed the impact of concomitant p53 or LKB1 loss on response to docetaxel monotherapy and combination therapy with selumetinib.
- Employed pharmacodynamic studies, including PET and CT imaging, to identify biological markers.
Main Results:
- Loss of p53 or LKB1 impaired response to docetaxel alone.
- Selumetinib plus docetaxel significantly benefited mice with KRAS and p53 mutations.
- Mice with KRAS and LKB1 mutations exhibited primary resistance to the combination therapy.
- Identified biological markers correlating with differential treatment efficacy across genotypes.
Conclusions:
- Concomitant loss of p53 or LKB1 influences response to targeted therapy in KRAS-mutant lung cancer.
- Selumetinib combination therapy shows genotype-specific efficacy, highlighting the importance of LKB1 status.
- Co-clinical trials can identify predictive genetic biomarkers and inform clinical trial design for lung cancer.
- This study supports the use of synchronous co-clinical trials to generate clinically relevant hypotheses.
