Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors inALK-Rearranged Lung Cancer

Abstract

Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib, alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation - ALK G1202R - increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.

Personalized therapy for lung cancer: Striking a moving target

“…The difference in potency likely explains the improved efficacy of the second-generation ALK inhibitors against brain metastasis relative to crizotinib, a common problem in ALK-driven NSCLC. Resistance mutations develop in 50% of patients treated with second-generation ALK TKIs and also increase when treated with more than one ALK TKI, suggesting that more potent inhibition not only leads to an increase in mutations, but also more specific alterations (60,65). Among the acquired mutations, the G1202R mutation appears to be the most difficult type to treat.…”

“…PI3K mutations have been detected in approximately 4% of resistant EGFR or ALK TKI-treated specimens, while loss of phosphatase and tensin homolog (PTEN), which inactivates phosphatidylinositol-3,4,5-triphosphate (PIP 3 ) signaling via dephosphorylation, has also been identified as a mechanism of EGFR resistance (65,108,109). However, the clinical role of the PI3K pathway in mediating resistance is not clear, as pathway alterations do not appear to affect TKI response in EGFR-mutated NSCLC patients nor cell survival in ALK-positive NSCLC cells (105,110).…”

“…Epithelial-to-mesenchymal transition (EMT) of tumors has been detected in EGFR TKI-and ALK TKIresistant NSCLCs facilitating migration and invasion, but the exact role of EMT in resistance remains unclear (44,65). While the mechanism of this transition has not been fully elucidated, AXL tyrosine kinase expression has been associated with it and IGF-1R has been noted to induce EMT in EGFR TKI-resistant cell lines (93,111).…”

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

“…With advancements in sequencing technology, multiple mutations in ALK have been discovered that convey either resistance or sensitivity. The mutation profile coverage varies among the next-generation ALK inhibitors [47]. Currently, knowing the resistance mutation does not impact the choice of postcrizotinib therapy, especially as mutations account for only one-third of resistance mechanisms.…”

“…Gainor et al evaluated post-progression biopsies of patients treated with second-generation ALK inhibitors and found that ALK resistance mutations were present in 56% of patients who progressed on second-generation ALK TKIs (compared to 20% of patients who progressed on crizotinib), with the most common being the G1202R mutation [47]. They proposed that in the setting of progression on a second-generation ALK inhibitor, repeat biopsy to assess for ALK mutations should be strongly considered as the presence of an ALK resistance mutation suggests that it remains the main oncogenic driver and the patient should be considered for further ALK -directed therapy.…”