Targeting ALK: Precision Medicine Takes on Drug Resistance

Abstract

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, including non-small cell lung cancer. However, the clinical benefit of targeting ALK using tyrosine kinase inhibitors (TKI) is almost universally limited by the emergence of drug resistance. Diverse mechanisms of resistance to ALK TKIs have now been discovered, and these basic mechanisms are informing the development of novel therapeutic strategies to overcome resistance in the clinic. In this review, we summarize the current successes and challenges of targeting ALK.

Significance: Effective long-term treatment of ALK-rearranged cancers requires a mechanistic understanding of resistance to ALK TKIs so that rational therapies can be selected to combat resistance. This review underscores the importance of serial biopsies in capturing the dynamic therapeutic vulnerabilities within a patient's tumor and offers a perspective into the complexity of on-target and off-target ALK TKI resistance mechanisms. Therapeutic strategies that can successfully overcome, and potentially prevent, these resistance mechanisms will have the greatest impact on patient outcome. Cancer Discov; 7(2); 137-55. ©2017 AACR.

Figure 1. Oncogenic ALK signaling

The ALK fusion protein is constitutively active and signals via phospholipase Cγ (PLCγ), JAK-STAT, RAS-RAF-MEK-ERK, and PI3K-AKT-mTOR pathways (13). This signaling results in the aberrant regulation of a number of genes (some of which are represented here), ultimately driving cell cycle progression, survival, proliferation, and angiogenesis (50). Secondary mutations in the ALK kinase domain (starred) cause acquired resistance to ALK TKIs. Several of the bypass signaling tracks implicated in ALK TKI resistance are also shown here —EGFR, HER2/HER3, MET, KIT, and IGF-1R with their respective ligands.

Figure 2. Experimental platforms for discovery and validation of TKI resistance mechanisms

Tumor biopsy specimens from patients obtained at baseline (pre-TKI), on TKI, and after relapse on a TKI (post-TKI) serve as the gold standard model for studying resistance mechanisms. Liquid biopsies with circulating tumor DNA (ctDNA) analyses are being increasingly utilized. Generation of patient-derived cell lines and xenografts (PDX), if successful, can help facilitate the execution of systematic functional assays. Based on the identified resistance mechanisms, novel therapeutic strategies may be developed and tested preclinically, prior to entering clinical trials.

Figure 3. Acquired resistance mechanisms to ALK TKIs

(A) The reported frequency of each secondary resistance mutation in the ALK kinase domain is depicted for post-crizotinib (n = 55), post-ceritinib (n = 24), post-alectinib (n = 17), and post-brigatinib (n = 7) cases, based on reference . The absence of a colored bar representing an ALK TKI (e.g., a blue bar representing brigatinib) indicates that the particular ALK mutation was not detected in the tested cases progressing after that specific ALK TKI (78). In (B) and (C), the differential frequency of ALK secondary mutations in crizotinib-resistant versus second-generation ALK TKI (e.g., ceritinib, alectinib, brigatinib)-resistant cases (20–30% versus 50–70%, respectively) is highlighted. Notably, the frequency of the G1202R mutation is significantly higher after relapse on a second-generation ALK TKI compared to crizotinib. ALK amplification appears to be an infrequent mechanism of resistance to second-generation ALK TKIs, although the exact frequency has not been determined (N.D.). WT = wild-type.

Figure 4. Guidelines for selecting treatment after progression on an ALK TKI

When patients have oligoprogression on an ALK TKI, local ablative therapies can be considered. (A) When patients have systemic relapse on crizotinib, repeat biopsies should ideally be pursued if feasible, as the detection of particular ALK resistance mutations in a small number of patients (e.g., I1171, F1174, or G1202R mutations) may impact the choice of next-generation ALK TKI. However, the absence of an ALK resistance mutation after crizotinib usually does not translate into ALK independence, and these patients should go on to be treated with a next-generation ALK inhibitor. (B) After relapse on a second- or later-generation ALK TKI, we strongly recommend repeat biopsies at the time of progression to determine the resistance mechanism. The detection of a secondary ALK resistance mutation is suggestive of continued ALK dependency of tumor cells, and therefore, sensitivity to another ALK TKI that has activity against the mutant kinase. If an ALK resistance mutation is not identified, resistance may have arisen due to bypass signaling, lineage changes, or other ALK-independent mechanisms. In these cases, the tumor cells are likely no longer ALK-dependent, and combinatorial approaches or standard chemotherapy may be more effective.