Current status and challenges of immunotherapy in ALK rearranged NSCLC

Abstract

Rearrangements of the anaplastic lymphoma kinase (ALK) gene account for 5-6% in non-small cell lung cancer (NSCLC). ALK rearranged NSCLC is sensitive to ALK tyrosine kinase inhibitors (TKIs) but prone to drug resistance. Meanwhile, ALK rearranged NSCLC has poor response to single immunotherapy. Here we mainly describe the immune escape mechanisms of ALK mutated NSCLC and the role of related biomarkers. Additionally, we collate and evaluate preclinical and clinical studies of novel immune combination regimens, and describe the prospects and perspectives for the in vivo application of novel immune technologies in patients with ALK rearranged NSCLC.

Keywords: ALK; NSCLC; immune checkpoint inhibitor; immunotherapy; process.

Figure 1

(A) A brief diagram of the ALK domain structure: MAM, Meprin, A5 protein and protein tyrosine phosphatase Mu domain; LDLa, Low-density lipoprotein receptor domain class A; G-rich, glycrine-rich region; TM, transmembrane helix; PTK, Receptor tyrosine kinase. (B) Summary diagram of the domain structure of human EML4: Primary (1°) sequence features: CC, coiled-coil; basic region; HELP, Hydrophobic motif found in EML proteins; WD repeats, Trp-Asp repeats. Tertiary (3°) structure features: TD, trimerisation domain; TAPE, tandem atypical propeller domain found in EML proteins. The TAPE domain N-terminal region is coloured teal and the C-terminal region is coloured canary yellow. (C) Schematic representation of EML4-ALK variant proteins:ALK PTK domain insertion into EML4 protein.

Figure 2

Circles in the figure represent keywords; Circle size represents frequency of occurrence of key words; The connection between the circle and the circle represents the relationship between the keywords, the coarser the connection is; Color represents time.

Figure 3

A simplified diagram of oncogenic signaling mechanisms of the ALK gene. Ras, rat sarcoma; Raf, rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; PI3K, Phosphoinositide 3-kinase; AKT, protein kinase B. mTOR, mechanistic target of rapamycin; JAK, Janus Kinase; STAT, Signal transducer and activator of transcription; PLC G, G protein-phospholipase C. IP3, Inositol triphosphates; PKC, Protein kinase C; DAG, Diacylglycerol.

Figure 4

Diagram of the mechanism of PD-L1 upregulation of EML4-ALK and NPM-ALK. (A) Diagram of the mechanism of PD-L1 upregulation in EML4-ALK mutant cancers. (B) Diagram of the mechanism of PD-L1 upregulation in NPM-ALK mutant cancers. PI3K, Phosphoinositide 3-kinase: AKT, protein kinase; MTOR, mechanistic target of rapamycin; Kras, Kirsten rat sarcoma; Raf, Rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; JAK, Janus Kinase; STAT, Signal transducer and activator of transcription; ALK, anaplastic lymphoma kinase; PD-L1, Programmed cell death 1 ligand 1.