Resistance to ALK inhibitors: Pharmacokinetics, mutations or bypass signaling?

KEYWORDS:

• Anaplastic lymphoma kinase
• alectinib
• acquired resistance
• ALK
• crizotinib
• ceritinib
• lung cancer
• STAT3

This article refers to:

STAT3-targeted treatment with silibinin overcomes the acquired resistance to crizotinib in ALK-rearranged lung cancer

The approval of multitargeted anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has been a success story for the management of advanced non-small-cell lung cancers (NSCLCs) over the last half a decade, with the 1st generation TKI crizotinib approved in 2011 and 2nd generation ALK TKIs approved (ceritinib in 2014 and alectinib in 2016) for crizotinib-resistant disease.^1-4 ALK rearrangements are present in 5% of NSCLCs and these fusion proteins act as driver oncogenes in those tumors; engaging pro-survival and anti-apoptotic signals through downstream signals including the phosphatidylinositol-3-kinase (PI3K), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) cascades. ALK TKIs disrupt the aforementioned signaling pathways and induce apoptosis.^5,6

The limitation of ALK TKI monotherapy is the inevitable development of tumor adaptation, also referred to as acquired resistance.⁷ Prior studies in preclinical models and patient-derived samples have indicated that resistance can occur by 3 main mechanisms: pharmacokinetic liabilities of a TKI, mutations that alter the kinase domain of ALK, or activation of other oncogenic signals within the tumor leading to bypass signaling.^6,7 For crizotinib, the main process explaining acquired clinical resistance seems to be pharmacokinetic (occurring over the course of continued daily therapy); with ALK mutations as a minor (∼20%) component.⁷ This type of resistance pattern explains why the more potent 2nd generation ALK TKIs – ceritinib and alectinib - with lower nanomolar inhibitory concentrations against ALK fusions with or without most ALK mutations are exceedingly active after crizotinib use.⁷ However, systemic disease resistance to 2nd generation ALK TKIs is usually biological⁷ with ∼55% of cases developing highly resistant ALK mutations (the most common ALK-G1202R) and the other ∼45% of cases likely developing bypass signaling (Fig. 1). Novel ALK TKIs with activity against ALK fusions with ALK-G1202R, including lorlatinib, are undergoing clinical development.⁷

Figure 1. Mechanisms of ALK inhibitor resistance and therapeutic strategies. (Top) Pie charts indicating frequencies of mechanisms of resistance to 1st (crizotinib) and 2nd generation (ceritinib or alectinib) ALK TKIs, modified from reference [7]. (Bottom) Flow chart of currently approved ALK TKIs, mechanisms of resistance, sequence of therapeutic targeting and possible avenues for clinical development of novel strategies.

In this volume of Cell Cycle, Dr. Cuyas and colleagues from the Catalan Institute of Oncology report on the activation of STAT3 as an important bypass signaling to ALK TKIs.⁸ They used a well-established preclinical model for ALK rearrangements with known epidermal growth factor receptor (EGFR) as the upstream crizotinib-resistant bypass oncogene,⁵ and show that the STAT3 pathway both mediates the bypass signaling resistance plus can be targeted using the STAT3 pharmacological inhibitor silibinin. Although the authors only used the 1st generation ALK TKI crizotinib, the same model has been shown to be resistant to 2nd generations ALK TKIs⁶; suggesting that upstream (mediated by EGFR or others) bypass signaling (through downstream STAT3 and/or MAPK and/or PI3K) is a common thread in ALK TKI-induced resistance. These data add to the preclinical work attempting to identify common downstream signaling cascades that could be clinical targets for development of therapies against ALK TKI-resistant lung tumors.⁷

The growing preclinical and clinical body of evidence points toward the need to develop novel approaches to both treat and/or prevent resistant to ALK TKIs in lung cancer; many which are beginning to translate into clinical trial development (Fig. 1) and may extend patient survival for this important group of NSCLCs.

Disclosure of potential conflicts of interest

DBC has received consulting fees from Pfizer Inc. (USA) and ARIAD Pharmaceuticals Inc. (USA); and honoraria from Boehringer Ingelheim Pharmaceuticals Inc. (Brazil). No other conflict of interest is stated.

Funding

This work was supported in part through an American Cancer Society grant (RSG 11-186), and a Lung Cancer Foundation of America- International Association for the Study of Lung Cancer grant.