• What is ALK?
  • ALK in Lung Cancer
  • ALK Mutations Resistant to ALK TKI Therapy
  • Clinical Trials

ALK

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; Janoueix-Lerosey et 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; Soda et 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; Soda et 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).

alk.png

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.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. ALK. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/alk/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

ALK in Non-Small Cell Lung Cancer (NSCLC)

Approximately 3–7% of lung tumors harbor ALK fusions (Koivunen et al. 2008; Kwak et al. 2010; Shinmura et al. 2008; Soda et al. 2007; Takeuchi et al. 2008; Wong et al. 2009). ALK fusions are more commonly found in light smokers (< 10 pack years) and/or never-smokers (Inamura et al. 2009Koivunen et al. 2008; Kwak et al. 2010; Soda et al. 2007; Wong et al. 2009). ALK fusions are also associated with younger age (Inamura et al. 2009; Kwak et al. 2010; Wong et al. 2009) and adenocarcinomas with acinar histology (Inamura et al. 2009; Wong et al. 2009) or signet-ring cells (Kwak et al. 2010). Clinically, the presence of EML4-ALK fusions is associated with EGFR tyrosine kinase inhibitor (TKI) resistance (Shaw et al. 2009).

Multiple different ALK rearrangements have been described in NSCLC. The majority of these ALK fusion variants are comprised of portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the ALK gene. At least nine different EML4-ALK fusion variants have been identified in NSCLC (Figure 1; Choi et al. 2008; Horn and Pao 2009; Koivunen et al. 2008; Soda et al. 2007; Takeuchi et al. 2008; Takeuchi et al. 2009; Wong et al. 2009). In addition, non-EML4 fusion partners have also been identified, including KIF5B-ALK (Takeuchi et al. 2009) and TFG-ALK (Rikova et al. 2007). Clinically, the presence of an ALK rearrangement is detected by fluorescence in situ hybridization (FISH) with an ALK break apart probe. FISH testing is not able to discern which particular ALK fusion is found in a clinical sample.

In the vast majority of cases, ALK rearrangements are non-overlapping with other oncogenic mutations found in NSCLC (e.g., EGFR mutations, KRAS mutations, etc.; Inamura et al. 2009; Kwak et al. 2010; Shinmura et al. 2008; Wong et al. 2009).

alk-fusions.png

Figure 1.
Schematic of ALK fusions found in lung cancer.

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

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

ALK Mutations Conferring Resistance to ALK TKI Therapy
Mutation Location within the kinase domain ALK fusion
1151Tins (Katayama et al. 2012) N terminal to the Cα-helix Not reported
L1152R (Sasaki et al. 2011) N terminal to the Cα-helix EML4-ALK E6;A20
C1156Y (Choi et al. 2010) N terminal to the Cα-helix EML4-ALK E13;A20
F1174La (Sasaki et al. 2010) C terminal to the Cα-helix RANBP2-ALK
L1196M (Choi et al. 2010; Doebele et al. 2012; Katayama et al. 2012; Kim et al. 2013) Gatekeeper mutation EML4-ALK E13;A20+
EML4-ALK E13;A20 (x1)
EML4-ALK E6;A20 (x1)
L1198Fb (Shaw et al. 2016) ATP binding pocket Not reported
G1202R (Katayama et al. 2012) Solvent front Not reported
S1206Y (Katayama et al. 2012) Solvent front Not reported
G1269A (Doebele et al. 2012; Kim et al. 2013) ATP binding pocket EML4-ALK E6;A19 (x1)
EML4-ALK E6;A20 (x1)
EML4-ALK E13;A20 (x2)
Implications for Targeted Therapeutics
Response to crizotinib (ALK/MET TKI) Confers decreased sensitivityc
Response to 2nd generation ALK TKIs Variabled
Response to HSP90 inhibitors Confers increased sensitivitye
Response to EGFR TKIs Unknown at this time
Response to anti-EGFR antibodies Unknown at this time

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" ALK TKIs.

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; Janoueix-Lerosey et 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 (Shaw et al. 2016).

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. 2011Katayama 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. 2013).

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. 2011Katayama et al. 2012). Further studies using HSP90 inhibitors in lung cancer patients who develop acquired resistance to crizotinib are ongoing. 


ALK_figure.png

Figure 1.
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 partners. 

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Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

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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