NcXHF

THE BATTLE AGAINST TKI RESISTANCE IN LUNG CANCER
Combating Acquired Resistance to Tyrosine Kinase Inhibitors in
Lung Cancer
Christine M. Lovly, MD, PhD
OVERVIEW
The prospective identification and therapeutic targeting of oncogenic tyrosine kinases with tyrosine kinase inhibitors (TKIs) has
revolutionized the treatment for patients with non–small cell lung cancer (NSCLC). TKI therapy frequently induces dramatic clinical
responses in molecularly defined cohorts of patients with lung cancer, paving the way for the implementation of precision medicine.
Unfortunately, acquired resistance, defined as tumor progression after initial response, seems to be an inevitable consequence of this
treatment approach. This brief review will provide an overview of the complex and heterogeneous problem of acquired resistance to
TKI therapy in NSCLC, with a focus on EGFR-mutant and ALK-rearranged NSCLC. In vitro models of TKI resistance and analysis of tumor
biopsy samples at the time of disease progression have generated breakthroughs in our understanding of the spectrum of mechanisms
by which a tumor can thwart TKI therapy and have provided an important rationale for the development of novel approaches to delay
or overcome resistance. Numerous ongoing clinical trials implement strategies, including novel, more potent TKIs and rational
combinations of targeted therapies, some of which have already proven effective in surmounting therapeutic resistance.
Therapeutic targeting of oncogenes has emerged as a preeminent
treatment paradigm for patients with non–
small cell lung cancer (NSCLC). Beginning in 2004 with the
initial identifıcation of epidermal growth factor receptor
(EGFR) mutations in a subset of lung adenocarcinomas, 1-3
molecular profıling of lung cancer, particularly lung adenocarcinoma,
has evolved into a complex spectrum of clinically
relevant and therapeutically actionable genomic alterations.
These alterations occur at varying frequencies and, at present,
have varying levels of clinical evidence to support the use
of targeted inhibitors in each setting. To date, the most welldescribed
molecular cohorts of NSCLC are those defıned by
the presence of EGFR mutations and ALK rearrangements.
Treatment for patients with EGFR-mutant and ALKrearranged
NSCLC with specifıc tyrosine kinase inhibitors
(TKIs) that target the EGFR and ALK tyrosine kinases, respectively,
has led to remarkable clinical responses, including
often-dramatic tumor shrinkage and increased progressionfree
survival (PFS) compared with standard cytotoxic
chemotherapy. 4-10
Unfortunately, despite the exciting results, virtually every patient
who receives TKI therapy and has an antitumor response
will eventually experience disease progression. This tumor relapse
while the patient is still receiving drug therapy is called acquired
resistance and typically occurs within 1 to 2 years after
the initiation of the TKI. 4-8,11,12 The development of drug resistance
remains a major limitation to the successful treatment for
patients with advanced NSCLC. Therefore, numerous preclinical
and clinical studies have been directed at identifying and understanding
on a mechanistic level the tumor-specifıc factors
that lead to acquired resistance in NSCLC. Given the complexity
of the topic, we will specifıcally focus in this review on EGFRmutant
and ALK-rearranged NSCLC as paradigms for the use of
targeted therapies and the battle to overcome acquired TKI resistance
in this disease.
EGFR-MUTANT NSCLC
EGFR is the gene that encodes for the EGFR tyrosine kinase.
EGFR propagates growth and survival signals through several
downstream pathways within the cell, including the RAS-RAF-
MEK-ERK (mitogen-activated protein [MAP] kinase) and the
phosphoinositide 3-kinase (PI3K)–AKT–mammalian target of
rapamycin (mTOR) pathways. In NSCLC, EGFR mutations are
typically detected in exons 18 to 21, which encode part of the
EGFR tyrosine kinase domain. Approximately 90% of these mutations
are small in-frame deletions in exon 19 or point mutations
in exon 21 (L858R). 13 These mutations activate EGFR
kinase activity and are typically detected in lung adenocarcinomas
with a frequency of approximately 10% of patients with
NSCLC in the United States and of approximately 35% in
Asia. 1-3
EGFR mutations confer sensitivity to and are strong predictors
of effıcacy for the EGFR TKIs. Several classes of EGFR
From the Division of Hematology-Oncology, Vanderbilt University School of Medicine, Nashville, TN.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Christine M. Lovly, MD, PhD, Division of Hematology-Oncology, Vanderbilt University School of Medicine, 2220 Pierce Ave. South, 777 Preston Research Building, Nashville,
TN 37232; email: christine.lovly@vanderbilt.edu.
© 2015 by American Society of Clinical Oncology.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e165