The anaplastic lymphoma kinase (ALK) is a
receptor tyrosine kinase that is aberrant in a variety of malignancies. For
example, activating missense mutations
within full length ALK are found in a subset of neuroblastomas (Chen et al. 2008;
George et al. 2008;
al. 2008; Mosse et al. 2008). By contrast, ALK
fusions are found in anaplastic large cell lymphoma (e.g., NPM-ALK; Morris et al. 1994),
colorectal cancer (Lin
et al. 2009; Lipson et al. 2012), inflammatory
myofibroblastic tumor (IMT; Lawrence et al. 2000) non-small
cell lung cancer (NSCLC; Choi et al. 2008; Koivunen et al. 2008;
Rikova et al. 2007;
al. 2007; Takeuchi et al. 2009), and ovarian cancer
(Ren et al. 2012).
All ALK fusions contain the entire ALK tyrosine kinase domain. To date, those tested
biologically possess oncogenic activity in vitro and in vivo (Choi et al. 2008;
Morris et al. 1994;
al. 2007; Takeuchi et al. 2009). ALK fusions and
copy number gains have been observed in renal cell carcinoma (Debelenko et al.
2011; Sukov et
al. 2012). Finally, ALK copy number and protein expression aberrations have also
been observed in rhabdomyosarcoma (van Gaal et al. 2012).
The various N-terminal fusion partners promote dimerization
and therefore constitutive kinase activity
(for review, see Mosse,
Wood, and Maris 2009). Signaling downstream of ALK fusions results in
activation of cellular pathways known to be involved in cell growth and cell proliferation
Figure 1. Schematic representation of ALK
fusions. "X" represents the various fusion partners that have been described. Dimerization of the ALK fusion mediated
by the fusion partner ("X"), results in constitutive activation of the ALK tyrosine kinase. ALK signaling results in
pro-growth and anti-apoptosis.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. ALK. My Cancer
(Updated December 7).
Last Updated: December 7, 2015
ALK in Non-Small Cell Lung Cancer (NSCLC)
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2014. ALK in Non-Small Cell Lung
Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/alk/
(Updated September 29).
Last Updated: September 29, 2014
ALK Mutations Associated with Acquired Resistance to ALK TKI Therapy
To date, several different point mutations
within the ALK tyrosine kinase domain have
been found in patients with acquired resistance to the ALK TKI, crizotinib. Figure 1 shows
the location of these mutations within the
ALK kinase domain.
Acquired resistance is defined clinically as progressive disease while on therapy after an
initial response. The mechanisms of acquired resistance to the ALK/MET TKI, crizotinib, are
incompletely understood at present. However, initial studies in small cohorts of patients
have already shown that mutations within
the ALK kinase domain can drive acquired
resistance to crizotinib. The mutations
described to date span the entire ALK kinase
domain and may confer variable degrees of sensitivity or resistance to "second-generation"
An EGFR L858R mutation and ALK
gene amplification have been reported in an ALK fusion positive patient with acquired
resistance to crizotinib, demonstrating that other genetic changes may underlie
crizotinib resistance (Kim et al. 2013).
Novel therapeutic strategies to attempt to overcome and/or prevent the development of
acquired resistance mutations in ALK
fusion positive lung cancer are currently being delineated.
a A patient with a crizotinib-sensitive inflammatory myofibroblastic
tumor harboring a RANBP2-ALK fusion was found to harbor an F1174L mutation at the time of progression (Sasaki et al. 2011).
The F1174L change is the same mutation found in patients with ALK-mutated neuroblastoma (Chen et al. 2008;
George et al. 2008;
al. 2008; Mosse et al. 2008).
b A patient with an ALK-rearranged lung cancer initially
responded to first-line crizotinib for 18 months but developed crizotinib resistance due to
the C1156Y mutation. The patient was then
treated with the third-generation ALK inhibitor, lorlatinib, as 6th line therapy. She had a
partial response lasting 8 months prior to the development of lorlatinib resistance.
Following the development of lorlatinib resistance, it was determined that the tumor had
acquired a second resistance mutation on
the same allele, L1198F, that
paradoxically also resensitized the tumor to crizotinib. The patient received crizotinib
again, demonstrating a clinically significant radiologic response for almost 6 months. In
vitro evidence indicates that L1198F confers greater resistance to second- and
third-generation inhibitors but is sensitizing to crizotinib in the context of a variety of
crizotinib-resistant mutation settings (Shaw et al. 2016).
c In most cases, mutations
confer resistance to crizotinib. However, a tumor harboring an ALK mutation associated with crizotinib resistance (C1156Y)
was shown to be resensitized to crizotinib after the acquisition of a second resistance
mutation on the same allele, L1198F, which confers resistance
to lorlatinib. L1198F appears to be resensitizing to crizotinib in the context of a variety
of crizotininb-resistant mutation settings
d"Second-generation" ALK TKIs have been demonstrated to have variable
efficacy against ALK kinase domain mutations associated with acquired
resistance to crizotinib (Katayama et al. 2011; Katayama et al. 2012).
In a cohort of 64 patients with crizotinib resistant ALK fusion positive lung
cancer, some of whom had documented "second site mutations" in the ALK tyrosine kinase
domain at the time of crizotinib resistance, an overall response rate of 73% was achieved
with the "second-generation" ALK TKI, LDK378 (Shaw et al.
e In vitro studies have demonstrated that the HSP90 inhibitor, 17-AAG,
can suppress the growth of both crizotinib-sensitive and -resistant ALK fusion positive lung
cancer cell lines (Katayama
et al. 2011; Katayama et al. 2012). Further studies
using HSP90 inhibitors in lung cancer patients who develop acquired resistance to crizotinib
Schematic of ALK kinase domain mutations associated with acquired
resistance to ALK TKI therapy. The top portion of the figure shows an expanded view of the
kinase domain of ALK, with ALK mutations noted underneath. The bottom
portion of the figure shows the ALK gene;
‘X’ denotes gene fusion
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2016. ALK Mutations Associated with Acquired Resistance to ALK TKI Therapy.
My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/alk/139/
(Updated May 12).
Last Updated: May 12, 2016
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