Transcript Background

Mechanisms of Acquired Resistance to
Epidermal Growth Factor Receptor Tyrosine
Kinase Inhibitors (EGFR-TKI) in Non-Small Cell
Lung Cancer (NSCLC)
Victor Cohen, MDCM, FRCPC
Department of Oncology
Segal Cancer Center
SMBD – Jewish General Hospital
McGill University
Background
• EGFR-TKI (gefitinib and
erlotinib)developed as therapeutic
agents for NSCLC
• Members of a class of Quinazolium-
derived agents
• Inhibit EGFR pathway by binding
(reversible) to ATP pocket domain
• Antitumor activity in clinical trials but
benefits modest
Background
• 10% of (Western) patients treated with
EGFR-TKI have dramatic and durable
responses
• Clinical features predicting sensitivity;
female, adenocarcinoma, Asian
ethnicity and never-smoking history
• 2004; EGFR mutations as a major
determinant underlying dramatic
responses following treatment with TKI
EGFR Mutations
EGFR Mutations
•
Mutations identified using DNA sequencing
methods
•
Considered the “gold standard”
•
Non-sequencing assays offering ease of
scoring and high sensitivity have been
developed
•
Providing a robust and accessible
approach to the rapid identification of
EGFR mutations
•
Denaturing High Performance Liquid
Chromatography (dHPLC)
EGFR Mutations
• Prospective trials treating therapy-
naïve patients with EGFR mutations
with EGFR-TKI (200 patients)
• RR 55-82% and median TTP of 9-13
months (3 to 4-fold greater than
observed with chemotherapy)
• Despite dramatic efficacy, all patients
will ultimately develop resistance
(acquired) to the agents
Acquired Resistance
•
Critical to understand mechanisms of
acquired resistance
•
May lead to the development of effective
therapies for patients who develop
acquired resistance
•
Acquired resistance mechanisms have
been studied most extensively in EGFR
mutant cancers
•
Remains to be determined if mechanisms
are shared with wild-type EGFR cancers
EGFR T790M Mutation
EGFR T790M Mutation
• Detected from tumors of EGFR mutant
NSCLC patients who have developed
clinical resistance (in vitro EGFR-TKI
resistant mutant cell lines)
• Found in 50% of tumors
• Analogous position to known
resistance mutations to imatinib in
other kinases; “gatekeeper mutation”
• ? Steric hindrance
Amplification of MET
Amplification of MET
• Redundant activation of Her3 permits
cells to transmit same downstream
signaling in the presence of EGFR-TKI
• Concomitant inhibition of both EGFR
and MET is required to kill resistant
cells
• 22% of NSCLC with acquired
resistance had MET amplification in
specimens
Acquired Resistance
•
EGFR T790M and MET amplification
account for 60-70% of all known causes of
acquired resistance to EGFR-TKI
•
Other mechanisms are likely to be
discovered
•
TGF-β IL-6 axis mediates selective and
adaptive mechanisms of resistance to
molecular targeted therapy in lung cancer*
* Yao et al. PNAS 35, 15535-40 (2010)
Acquired Resistance
• Existence of subpopulation of cells
intrinsically resistant to EGFR-TKI
• Display features of EMT
• Activation of TGF-β mediated signaling
was sufficient to induce EMT
phenotypes
• Upregulation of TGF-β resulted in
increased secretion of IL-6 (cells
resisted treatment independently of
EGFR pathway)
Acquired Resistance
•
Produced during inflammatory response
•
Mouse model used to determine whether
inflammation might impair sensitivity
•
Induction of inflammation stimulated IL-6
secretion and was sufficient to decrease
tumor response
•
Data provide evidence indicating
resistance could arise not only as a
consequence of changes within cells but
also through activation of tumor
microenvironment
Challenges
• Important to continue to study
preclinical models (and tumors) that
have developed resistance to uncover
novel resistance mechanisms
• Several challenges in translating
preclinical studies into effective
clinical therapies
Challenges
• Accurately identifying which patients
have which mechanisms of resistance
• No repeated tumor biopsies
• Critical in that the therapeutic strategy
aimed at overcoming resistance may
not be effective in all resistant patients
E.g. Irreversible inhibitors not effective in
resistance mediated by MET amplification
Challenges
•
Multiple mechanisms of resistance can
occur concurrently in same patient
•
Both EGFR T790M and MET have been
detected in same specimens (occur
independently in different metastatic sites
in the same patient)
•
Therapeutic strategy aimed solely at one
mechanism may not be effective or lead
only to partial regressions
•
Combination strategies may be more
comprehensive and potentially more
effective
Challenges
• Biological definition and detection of
resistance mechanisms
• T790M can sometimes be present as
minor allele and yet be sufficient to
cause resistance but may go
undetected
• Challenges with detection of MET
amplification. Definition of what
constitutes clinically significant
amplification not well defined
Conclusion
•
Gefitinib and erlotinib are effective
therapies for patients with EGFR mutant
NSCLC
•
All patients ultimately develop resistance
•
Important to identify and study
mechanisms of resistance as a means of
rationally designing the next generation
clinical studies
•
Several clinical trials (aimed at inhibiting
known resistance mechanisms) are
already underway