Multiple advances have been made in the treatment of lung cancer
during the last several years, including the development of
novel targeted and chemotherapeutic agents. Despite this,
overall survival for lung cancer remains low. Lung cancer is a
heterogeneous disease, and there is a great deal of interest in
personalization of therapy. This requires careful coordination
between the bench and the clinic to identify potential novel
therapeutic targets, and to better select patients for treatment.
Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic
lymphoma kinase (ALK), EGFR, and MET, along with other key drivers
in lung cancer carcinogenesis, could represent such targets.

The incidence of EML4-ALK in NSCLC appears to be low, with a
frequency of 1% to 7% in reported studies. Despite the relatively
low frequency, EML4-ALK NSCLC appears to represent a distinct subset
of patients. In the largest series to date, NSCLC patients with at
least two of the following characteristics were selected for genetic
screening: female sex, Asian ethnicity, never/light smoking history,
and adenocarcinoma histology. Investigators screened 141 tumors,
and 19 patients were found to carry EML4-ALK mutations; 31 carried
EGFR mutations. Consistent with the previous literature, EML4-ALK and
EGFR mutations were mutually exclusive. Interestingly, the patients
carrying EML4-ALK mutations were significantly younger and more likely
to be men than were patients with EGFR mutations or those who carried
wild type (WT) for both genes. Although EML4-ALK has been reported in
smokers, in this particular study, participants with EML4-ALK, like
those with EGFR mutations, were more likely to be never/light smokers
than were those carrying WT (p<0.001).

Most importantly, EML4-ALK may potentially serve as a novel therapeutic
target in NSCLC. Currently, patients with EML4-ALK appear to have both
a similar response rate to platinum-based chemotherapy and overall survival
compared to WT patients. Most recently, a phase I trial of the ALK inhibitor
PF-02341066 has shown promising activity in patients whose tumors harbor the
EML4-ALK fusion gene. Of 19 NSCLC patients with EML4-ALK, 10 (53%) had a
partial response. Larger trials are currently ongoing, and will be important
in confirming the benefit seen in this early-phase study.

There has been considerable interest in the role MET amplification may play
in resistance to therapeutic inhibition with EGFR tyrosine kinase inhibitors
(TKIs). Resistance to therapy is a complex process, and can occur through
different mechanisms. It is often caused by additional acquired mutations;
one of the most extensively studied is T790M, which alters the confirmation
of the tyrosine kinase domain, preventing binding of erlotinib and gefitinib.
Additionally, MET amplification may lead to acquired resistance to EGFR TKIs
through ERBB3 activation of PI3K in up to 20% of patients. This finding
potentially has important therapeutic implications for patients treated with
EGFR TKIs who then experience failure during therapy. Several MET inhibitors
are in early-phase trials, and studies looking at strategies for dual inhibition
of EGFR and MET as a potential mechanism to overcome resistance are currently
ongoing.

With the extensive use of EGFR-targeted inhibitors and translational research
efforts in parallel for the last few years, it is becoming clear that there are
molecular genetic differences in lung cancer genes, such as EGFR, among different
human populations. Importantly, these differences can modulate treatment sensitivity
and resistance, and thus also affect novel therapeutic efficacies. Further data
emerging in the field is now readily available on other lung cancer proto-oncogenes
and racial differences, such as in c-Met proto-oncogene (MET) and ALK (anaplastic
lymphoma kinase) (echinoderm microtubule-associated protein-like 4 [EML4]-ALK),
as well as in tumor suppressor genes, such as serine/threonine kinase 11 (LKB1).

The treatment of lung cancer remains complex and challenging. Although significant
advances have been made, much remains unknown about the molecular biology of this
disease. Novel approaches to diagnosis and therapy are needed, and the findings
reviewed here represent clear promise for the future.

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