Acquired resistance to targeted therapies in NSCLC: Updates and evolving insights

Abstract

While significant advancements have been made in the available therapies for metastatic non-small cell lung cancer (NSCLC), acquired resistance remains a major barrier to treatment. We have not yet achieved the ability to cure advanced NSCLC with systemic therapy, despite our growing understanding of many of the oncogenic drivers of this disease. Rather, the emergence of drug-tolerant and drug-resistant cells remains the rule, even in the face of increasingly potent targeted therapies. In this review, we provide a broad overview of the mechanisms of resistance to targeted therapy that have been demonstrated across molecular subtypes of NSCLC, highlighting the dynamic interplay between driver oncogene, bypass signaling pathways, shifting cellular phenotypes, and surrounding tumor microenvironment.

Keywords: Acquired resistance; Non-small cell lung cancer (NSCLC); Targeted therapies; Tumor microenvironment.

Figure 1

There are three major categories of tumor cell-intrinsic mechanisms of acquired resistance to targeted therapies: on-target resistance, bypass pathway activation, and lineage transformation. On-target resistance and bypass pathway activation maintain reliance on core downstream signaling pathways of the driver oncogene and develop via genetic alterations such as secondary kinase mutations and gene amplification. Lineage transformation is a form of phenotypic plasticity that involves cellular reprogramming and decreased activity of signaling pathways critical to the driver oncogene.

Figure 2

Schema outlining the role of the tumor microenvironment (TME) in mediating acquired resistance to targeted therapies. Proposed mechanisms include paracrine signaling (resulting in activation of bypass RTK signaling) and CAF-mediated collagen production, alteration of the extracellular matrix, and induction of lineage transformation.