ALK-positive lung cancer: a moving target

Abstract

Anaplastic lymphoma kinase (ALK) is a potent oncogenic driver in lung cancer. ALK tyrosine kinase inhibitors yield significant benefit in patients with ALK fusion-positive (ALK⁺) lung cancers; yet the durability of response is limited by drug resistance. Elucidation of on-target resistance mechanisms has facilitated the development of next-generation ALK inhibitors, but overcoming ALK-independent resistance mechanisms remains a challenge. In this Review, we discuss the molecular underpinnings of acquired resistance to ALK-directed therapy and highlight new treatment approaches aimed at inducing long-term remission in ALK⁺ disease.

Fig. 1 |. Oncogenic ALK signaling.

Left, wild-type ALK is a plasma membrane-bound RTK that undergoes autophosphorylation upon ligand binding and receptor oligomerization. ALK activates downstream signaling pathways that contribute to organ development and homeostasis. Right, a chromosomal translocation leads to formation of an ALK fusion gene and translation of an ALK chimeric oncoprotein that is composed of the C-terminal kinase domain of ALK joined with various N-terminal, non-kinase fusion partners. Constitutive activation of ALK promotes cell survival pathways and tumorigenesis. Although many ALK binding partners have been elucidated across all tumor types, the EML4–ALK fusion is the most common, of which EML4-ALK variant 1 (E13;A20) and variant 3 (E6;A20) are the most prevalent in lung cancer. FDA-approved ALK TKIs and their generation are depicted. PDK1, pyruvate dehydrogenase kinase 1; v, variant; 1G, first generation; 2G, second generation; 3G, third generation.

Fig. 2 |. Resistance in ALK⁺ lung cancer and therapeutic interventions.

Resistance to ALK TKIs occurs through three main mechanisms. Left, on-target resistance is mediated by mutations in the ALK tyrosine kinase domain, which disrupt TKI binding to ALK, rendering tumor cells insensitive to ALK inhibition. ALK residues involved in ALK TKI resistance are listed. Single ALK mutations are most common after first- or second-generation ALK TKIs, while compound mutations are most common after sequential use of early-generation inhibitors culminating with a third-generation inhibitor, lorlatinib. This stepwise accumulation of ALK mutations confers resistance to ALK TKIs, with fourth-generation (4G) ALK TKIs designed to target compound mutations that are refractory to current FDA-approved ALK inhibitors. Middle, off-target resistance is mediated by bypass signaling activation or lineage transformation. Bypass pathway activation can occur through genetic mechanisms (amplifications, activation mutations, structural alterations) and non-genetic mechanisms (receptor hyperactivation), resulting in activation of signaling pathways that bypass ALK dependency. Rational combinations of ALK plus bypass pathway inhibition are being evaluated and are depicted in gray boxes. Right, lineage transformation is another off-target resistance mechanism that can lead to ALK TKI insensitivity. Diagnostic biopsies to define histology are necessary to select histology-specific chemotherapy regimens in squamous cell- or small cell-transformed tumors. Studies are underway to determine whether histologic changes are reversible and whether epigenetic modifiers may resensitize tumor cells to ALK inhibition. GRB2, growth factor receptor-bound protein 2; PTEN, phosphatase and tensin homolog; Rheb, Ras homolog enriched in brain; SOS, son of sevenless; SHP2, SH2 containing protein tyrosine phosphatase-2; TSC, tuberous sclerosis proteins 1 and 2; WT, wild type.

Fig. 3 |. Forward-looking treatment paradigms in advanced ALK⁺ lung cancer.

Top, sequential ALK TKI therapy culminating in lorlatinib induces compound ALK mutations, with ALK^G1202R- or ALK^I1171N-based compound mutations being the most common. The schematic depicts tumor clonal evolution with the multitude of single ALK mutations serving as a substrate for compound ALK mutations, highlighting the notion of stepwise accumulation of resistance mutations. Treatment with a highly potent pan-inhibitory third-generation ALK TKI in the first-line (1L) setting may allow for maximal cytoreduction and depth of response, limiting tumor heterogeneity that can emerge with less potent ALK TKIs. Middle, drug-tolerant cells that are present at the time of treatment may undergo expansion under therapeutic selective pressure, leading to treatment failure and clinical relapse. In parallel, persister cells that survive initial treatment may acquire de novo resistance alterations, serving as a nidus for the development of polyclonal resistance. Depicted in gray are potential adjunctive therapeutic strategies aimed at eliminating persister cells. Bottom, intratumoral heterogeneity can occur across different regions of the primary tumor and/or metastatic sites, with spatial heterogeneity represented by the presence of subclones with different genetic features. Intertumoral heterogeneity can also occur across different metastatic sites, which can be missed using single-site tissue biopsies. Studies are underway to evaluate the utility of early rational combinations and to stem polyclonal resistance. In parallel, efforts are ongoing to develop ultrasensitive diagnostic tools to track tumor response and detect microscopic disease. 2L, second line; 3L, third line.