The Dual Role of Autophagy in Crizotinib-Treated ALK+ ALCL: From the Lymphoma Cells Drug Resistance to Their Demise.

Estelle Espinos,Sylvie Giuriato,Raymond Lai

doi:10.3390/cells10102517

Abstract

Autophagy has been described as harboring a dual role in cancer development and therapy. Depending on the context, it can exert either pro-survival or pro-death functions. Here, we review what is known about autophagy in crizotinib-treated ALK+ ALCL. We first present our main findings on the role and regulation of autophagy in these cells. Then, we provide literature-driven hypotheses that could explain mechanistically the pro-survival properties of autophagy in crizotinib-treated bulk and stem-like ALK+ ALCL cells. Finally, we discuss how the potentiation of autophagy, which occurs with combined therapies (ALK and BCL2 or ALK and RAF1 co-inhibition), could convert it from a survival mechanism to a pro-death process.

Highlights

We found that the potentiation of autophagy resulted in a strong loss of viability, but with no potentiation of apoptosis, suggesting that another cell death pathway may account for cell killing
We found that Rapidly Accelerated Fibrosarcoma 1 (RAF1) pharmacological inhibition or molecular downregulation potentiated the crizotinib-induced autophagic flux, which was associated with a loss in cell viability and increased apoptosis [17]
Anaplastic large cell lymphoma (ALCL) cells [102]; (ii) by limiting the presentation of tumor-specific antigen through the downregulation of human leucocyte antigen (HLA) molecules; a recent study reported that the inhibition of the anaplastic lymphoma kinase (ALK) oncogene induced elevated transcript and protein expression of HLA class I, consistent with its increased representation at the cell surface [103], and the ALK oncogene may allow lymphoma cells to evade the immune system by downregulating the expression of HLA class I molecules; (iii) by expressing immunosuppressive factors such as immune checkpoints, which inhibit the activity of tumor-associated T cells

Summary

Introduction

Anaplastic large cell lymphoma (ALCL) is a rare type of T-cell lymphoma, accounting for approximately 3% of adult non-Hodgkin lymphomas and 10 to 20% of childhood lymphomas [1]. As reported for other TKIs, escape mechanisms that allow cancer cells to overcome the effects of crizotinib have emerged [8,9] This led to both the development of a new generation of TKI inhibitors [10,11] as well as a diverse range of combined therapies, in an attempt to preempt relapses and to eradicate the malignant cells [12,13]. ALK+ ALCLprotocol patients or who areexperienced either refractory to theresearch gold standard protocol toward or who the experienced relapses, who relapses, efforts ALCL99 were conducted development of research efforts weretargeted conducted the development targeted and combined therapies.

Initial Findings

Combined ALK and BCL2 Inactivation

Combined ALK and RAF1 Inactivation

Autophagy as a Great Orchestrator of Cell Fate

Impairment of Apoptosis

Autophagy and Cancer Stemness

Selective Removal of Pro-Survival Substrates or Anti-Apoptotic Factors

Scaffold for Cell Death Complexes

Reconstitution of Immune Surveillance

Findings

Conclusions