Evidence Suggesting That Discontinuous Dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors

Abstract

The anaplastic lymphoma kinase ALK is chromosomally rearranged in a subset of certain cancers, including 2–7% non-small cell lung cancers (NSCLC) and ~70% of anaplastic large cell lymphomas (ALCL). The ALK kinase inhibitors crizotinib and ceritinib are approved for relapsed ALK+ NSCLC, but acquired resistance to these drugs limits median progression-free survival on average to ~10 months. Kinase domain mutations are detectable in 25–37% of resistant NSCLC samples, with activation of bypass signaling pathways detected frequently with or without concurrent ALK mutations. Here we report that, in contrast to NSCLC cells, drug resistant ALCL cells show no evidence of bypassing ALK by activating alternate signaling pathways. Instead, drug resistance selected in this setting reflects upregulation of ALK itself. Notably, in the absence of crizotinib or ceritinib, we found that increased ALK signaling rapidly arrested or killed cells, allowing a prolonged control of drug-resistant tumors in vivo with the administration of discontinuous rather than continuous regimens of drug dosing. Furthermore, even when drug resistance mutations were detected in the kinase domain, overexpression of the mutant ALK was toxic to tumor cells. We confirmed these findings derived from human ALCL cells in murine pro-B cells that were transformed to cytokine independence by ectopic expression of an activated NPM-ALK fusion oncoprotein. In summary, our results show how ALK activation functions as a double-edged sword for tumor cell viability, with potential therapeutic implications.

Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency

“…7D). These results are in accordance with recent data reported by Amin et al on regression in mice of NPM-ALK amplified ALCL xenografts upon TKI treatment suspension 28 . These results suggest that ALK TKI resistance mediated by ALK amplification could be tamed by cycles of drug suspension, a so-called “drug holiday” where ALK amplified cells would die under an oncogenic stress-mediated DNA damage.…”

“…We and others recently described genomic amplification of the ALK locus as a mechanism of ALK TKI resistance 26, 28 . We reported three ALK-rearranged cell lines (K299AR300A, K299AR300B, K299AR300C) whose resistance to the ALK inhibitor brigatinib was mediated by genomic amplification that caused NPM-ALK overexpression (Fig.…”

“…Thus, in line with other cases of resistance, such as B-Raf, BCR-ABL, and others 31-34, 49 , our data suggest that patients that have developed resistance to ALK TKI mediated by NPM-ALK amplification might benefit from cycles of administration and suspension of TKI treatment, the so called “drug holiday” therapy (Fig.8) 50, 51 . Recently, a drug holiday approach for NPM-ALK amplified ALCL was also proposed by Amin et al with experiments in xenograft mouse models 28 .…”

“…To date most of the data on the mechanisms of resistance to ALK TKI have been collected in NSCLC patients 20-23 , whereas very few data are available for ALCL. Mechanisms of acquired resistance to ALK TKI in ALK-rearranged ALCL have been described mainly in vitro by our group and others, including single point mutations of the TK domain and amplification of the ALK fusion gene 24-28 . Amplification of the ALK fusion gene has also been described in ALK-rearranged NSCLC and leads to increased expression of the oncogenic ALK fusion that requires increasing dosage of ALK TKI to be treated.…”

From bench to bedside: the past, present and future of therapy for systemic paediatric ALCL, ALK+

“…As with other TKIs, resistance is expected, and has indeed been observed, sometimes with aggressive relapses in isolated cases (Gambacorti‐Passerini et al , ). It may be that ALK TKIs should be given on a long‐term basis, possibly on a metronomic schedule to improve control of tumour progression (Amin et al , ). It may also be that combination therapies could alleviate the risk of relapse, indeed recent data in experimental settings show synergies between either NOTCH inhibitors and ALK TKIs (Larose et al , ), or ALK TKIs and BV (Hudson et al , ).…”