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Updated: Oct 6, 2025
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Published on: November 22, 2021
Histological and molecular plasticity of ALK-positive non-small-cell lung cancer under targeted therapy: a case
Markus Ball1,2, Petros Christopoulos2,3, Martina Kirchner1
1Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Abstract:
With medical progress in cancer therapy, tyrosine kinase inhibitors (TKIs) became a standard of care for many cancer types. But the broad range of possible targeted therapies was accompanied by a plethora of potential resistance mechanisms, of which many have still to be identified. Here, we present the case of a patient with an EML4-ALK translocated non-small-cell lung cancer treated with four different TKIs. Her tumor developed not only a well-known ALK-TKI resistance mutation but also underwent a histological transformation from adenocarcinoma to squamous cell carcinoma. To confirm a shared monoclonal origin of the phenotypically different tumors, a phylogenetic reconstruction was conducted: This revealed a cluster of mutations including NFE2L2, KMT2D, and MLH1, which are possible triggering events for the transformation.
Insights
Tyrosine kinase inhibitors (TKIs) treat cancer but can lead to resistance. This study details a non-small cell lung cancer case that transformed histologically and developed resistance mutations during TKI therapy.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Tyrosine kinase inhibitors (TKIs) are crucial in targeted cancer therapy.
- Identifying resistance mechanisms is vital for improving treatment efficacy.
- Non-small cell lung cancer (NSCLC) with EML4-ALK translocations is a key area for TKI development.
Observation:
- A patient with EML4-ALK NSCLC received four different TKIs.
- The tumor exhibited acquired resistance via an ALK mutation.
- Histological transformation from adenocarcinoma to squamous cell carcinoma was observed.
Findings:
- Phylogenetic analysis confirmed a shared monoclonal origin for both tumor phenotypes.
- Mutations in NFE2L2, KMT2D, and MLH1 were identified.
- These mutations are potential drivers of the observed histological transformation.
Implications:
- This case highlights complex resistance mechanisms beyond simple mutations.
- Understanding transformation drivers can inform future therapeutic strategies.
- Further research into combined mutations and histological changes is warranted for advanced NSCLC.
