ALK Resistance Mechanisms

ALK+ NSCLC resistance mechanisms

Multiple mechanisms may promote resistance to ALK+ NSCLC1

Chart showing resistance mechanisms to ALK-positive NSCLC

Reused with permission. © 2014 American Society of Clinical Oncology. All rights reserved.

ALK-dependent mechanisms, such as secondary mutations of the ALK kinase domain and amplification of the ALK fusion gene, may promote resistance1

  • The gatekeeper mutation L1196M is the most commonly reported resistance mutation believed to impact the ALK kinase domain1,2
  • Other mutations such as C1156Y, G1202R, S1206Y, L1152R, F1174L, G1269A, and 1151Tins may also play a role in resistance1,3,4

Resistance may also be driven by ALK-independent mechanisms such as the activation of alternative signaling pathways2

Activation of alternative pathways bypasses ALK 2

ALK alternative pathway activation diagram

Adapted by permission from Macmillan Publishers Ltd: Solomon B, Wilner KD, Shaw AT. Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin Pharmacol Ther. 2014;95:15-23, copyright 2014.

  • Upregulation of EGFR-signaling has been observed in resistant ALK+ cell lines2
  • Increased EGFR activation has been detected in patients with ALK+ NSCLC who developed resistance3
  • Other mechanisms, including c-KIT and KRAS, have also been identified as potential bypass tracks in resistance1

ALK=anaplastic lymphoma kinase; CNS=central nervous system; EGFR=epidermal growth factor receptor; ERK=extracellular signal-regulated kinase; KRAS=V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; NSCLC=non-small cell lung cancer; PI3K=phosphatidylinositol 3-kinase; RTK=receptor tyrosine kinase; STAT=signal transducer and activator of transcription.

References

  1. Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol. 2013;31:1105-1111. PMID: 23401436
  2. Solomon B, Wilner KD, Shaw AT. Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin Pharmacol Ther. 2014;95:15-23. PMID: 24091716
  3. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4:120ra17. doi:10.1126/scitranslmed.3003316. PMID: 22277784
  4. Kodama T, Tsukaguchi T, Yoshida M, Kondoh O, Sakamoto H. Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance. Cancer Lett. 2014;351:215-221. PMID: 24887559