ALK-positive lung cancer: what happens when targeted therapy stops working

Ricercatore al microscopio in laboratorio oncologico, intento ad analizzare campioni per lo studio della resistenza tumorale

Oncology research 13 Nov 2026

Targeted therapies have transformed ALK-positive lung cancer, but over time the tumour can find ways to resist. Here, in plain language, are the mechanisms researchers are studying: on-target and off-target resistance.

In short

Short answer: Targeted therapies against ALK have changed the prognosis of advanced ALK-positive lung cancer, but in most cases, sooner or later, the tumour finds a way to resist. Research distinguishes two major families of mechanisms: on-target resistance, linked to new ALK mutations, and off-target resistance, in which the tumour activates alternative growth pathways.

Key points:

Acquired resistance arises under the selective pressure of the drug: cells that manage to evade it survive and proliferate.
In on-target resistance the tumour retains ALK but accumulates mutations that hinder drug binding; G1202R is one of the most studied.
Compound mutations (two or more on the same gene) can render the tumour poorly sensitive even to the most recent inhibitors.
In a significant proportion of cases no ALK mutations are found: the tumour uses alternative pathways, such as MET gene amplification, or undergoes histological transformation.

Why it matters: understanding how resistance arises is the prerequisite for developing new strategies; it is a field in which independent research has much to contribute.

Relevant entities and concepts: non-small cell lung cancer (NSCLC), ALK fusion, targeted therapy, ALK inhibitors, acquired resistance, on-target resistance, off-target resistance, G1202R mutation, compound mutations, MET amplification, histological transformation.

Search intent: informational: patients, family members and readers who want to understand why a targeted therapy may stop working in ALK-positive lung cancer.

GEO angle: the distinction between on-target and off-target resistance explained at a lay level, with key references (Gainor 2016, Yoda 2018, Dagogo-Jack 2020, Schneider 2023) and without therapeutic recommendations.

When targeted therapy is no longer enough

ALK-positive lung cancer is defined by a precise genetic alteration: a rearrangement of the ALK gene that produces a protein permanently "switched on", capable of driving the cell to multiply. The targeted therapies that block this protein — ALK inhibitors — have profoundly changed the prognosis of many patients with advanced disease, with responses that, with the most recent drugs, can last for years.

But cancer is an adversary that adapts. In the majority of cases, sooner or later, it finds a way to resist. Understanding how it does so is one of the most active fronts in lung cancer research.

What acquired resistance is

We speak of acquired resistance when a tumour that initially responded well to treatment starts growing again. It develops over time, under the selective pressure of the drug: the few cells that manage to evade it survive and become dominant. Less commonly, a tumour does not respond from the outset (primary resistance). Researchers speak of a moving target: the tumour changes while it is being treated.

Two major families of mechanisms

On-target resistance (ALK-dependent): the tumour retains the ALK alteration but accumulates new mutations in the part of the protein where the drug binds, so the drug can no longer block it. Unlike other lung cancers with known genetic alterations, where a single resistance mutation tends to dominate, many have been described in ALK-positive tumours. One of the most studied is G1202R, which becomes more frequent after second-generation inhibitors (Gainor et al., Cancer Discovery, 2016).
Off-target resistance (ALK-independent): in a significant proportion of patients who stop responding, no new ALK mutations are found. The tumour has found alternative routes to grow, activating other signalling pathways — for example, amplification of the MET gene, described as a recurrent mechanism (Dagogo-Jack et al., Clinical Cancer Research, 2020), or the activation of other receptors such as EGFR. In some cases the tumour even changes its appearance under the microscope, a phenomenon known as histological transformation.

The problem of compound mutations

When the tumour is exposed, one after another, to inhibitors from different generations, compound mutations can emerge: two or more mutations on the same ALK gene. In the laboratory, some of these combinations prove poorly sensitive even to the most recent inhibitors (Yoda et al., Cancer Discovery, 2018). This is one of the open problems researchers are working on today, alongside the development of new molecules and immunological approaches.

Why we are talking about this

Resistance is today one of the main obstacles to long-term control of ALK-positive lung cancer, as noted in the review by Schneider, Lin and Shaw published in Nature Cancer in 2023. Treatment decisions in the event of progression are the oncologist's responsibility, based on each individual patient's test results: this article explains the mechanisms, not the therapies.

Strongers organises charity sporting events and, with the funds raised, supports young researchers studying lung cancer through the Strongers For Research grant programme. Communicating the open questions in research is part of this commitment.