Response to Chemotherapy, Reexposure to Crizotinib and Treatment with a Novel ALK Inhibitor in a Patient with Acquired Crizotinib Resistance

Schrödl, Kathrin; Schilling, Christoph von; Tufman, Amanda; Huber, Rudolf M.; Gamarra, Fernando

doi:10.1159/000364949

Cited by 11 publications

(10 citation statements)

References 11 publications

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“…In lung cancer, EML4-ALK copy-number gain and increased expression are reported in association with crizotinib resistance (18, 19). There are recent case reports of ALK+ NSCLC patients who became refractory to crizotinib obtaining secondary responses upon re-challenge after a period off the drug (45, 46). Both patients, however, received chemotherapy upon initial crizotinib discontinuation, so we do not know if ALK overdose was present or might have led to spontaneous regressions if they had been observed without therapy.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…Also, patients with acquired EGFR T790M resistance mutations who are taken off drug demonstrate loss of this mutation in their tumors, which may explain why these patients respond upon retreatment with EGFR inhibitors that do not target the T790M mutation . Similar retreatment effects are also seen with crizotinib . Such findings must be interpreted carefully, as drug holidays prior to the acquisition of resistance may actually speed the resistance process ; however, in total, these results suggest the optimization of dosing regimens for oncogene‐targeted therapeutics is never ‘one size fits all.’ Optimal dosing schedules should be actively explored in preclinical models and inform the clinical testing of distinct dosing hypotheses in patients.…”

Section: A Road Map For Targeting Oncogene Addictionmentioning

confidence: 94%

Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure

2015

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A key goal of cancer therapeutics is to selectively target the genetic lesions that initiate and maintain cancer cell proliferation and survival. While most cancers harbor multiple oncogenic mutations, a wealth of preclinical and clinical data supports that many cancers are sensitive to inhibition of single oncogenes, a concept referred to as 'oncogene addiction'. Herein, we describe the clinical evidence supporting oncogene addiction and discuss common mechanistic themes emerging from the response and acquired resistance to oncogene-targeted therapies. Finally, we suggest several opportunities toward exploiting oncogene addiction to achieve curative cancer therapies.

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“…However, two case reports have shown that patients may respond positively to rechallenge with crizotinib, lending support to the clinical investigation of discontinuous dosing with ALK TKIs. 74 , 75 …”

Section: Intermittent Dosingmentioning

confidence: 99%

Oncogene Overdose: Too Much of a Bad Thing for Oncogene-Addicted Cancer Cells

et al. 2015

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Acquired resistance to targeted inhibitors remains a major, and inevitable, obstacle in the treatment of oncogene-addicted cancers. Newer-generation inhibitors may help overcome resistance mutations, and inhibitor combinations can target parallel pathways, but durable benefit to patients remains elusive in most clinical scenarios. Now, recent studies suggest a third approach may be available in some cases—exploitation of oncogene overexpression that may arise to promote resistance. Here, we discuss the importance of maintaining oncogenic signaling at “just-right” levels in cells, with too much signaling, or oncogene overdose, being potentially as detrimental as too little. This is highlighted in particular by recent studies of mutant-BRAF in melanoma and the fusion kinase nucleophosmin–anaplastic lymphoma kinase (NPM–ALK) in anaplastic large cell lymphoma. Oncogene overdose may be exploitable to prolong tumor control through intermittent dosing in some cases, and studies of acute lymphoid leukemias suggest that it may be specifically pharmacologically inducible.

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Response to Chemotherapy, Reexposure to Crizotinib and Treatment with a Novel ALK Inhibitor in a Patient with Acquired Crizotinib Resistance

Cited by 11 publications

References 11 publications

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

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

Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure

Oncogene Overdose: Too Much of a Bad Thing for Oncogene-Addicted Cancer Cells

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