In brief
- A commentary in Cancer Discovery by Xiuning Le and Jürgen Wolf argues that, beyond the established rare fusions such as ALK and ROS1, ultrarare fusions involving receptor tyrosine kinases or their ligands are guiding the discovery of novel mechanisms of oncogenic activation and of corresponding treatment strategies.
- Its occasion is a study by Zheng and colleagues in the same issue, which identified an EGFR-SHC1 fusion subtype in non-small cell lung cancer that resists EGFR tyrosine kinase inhibitor monotherapy.
- Zheng and colleagues report that the fusion protein simultaneously activates the EGFR kinase domain and SRC-mediated phosphorylation of the SHC1 partner, together driving ERK and AKT pathway activation independently of kinase-domain inhibition.
- Afatinib combined with the SRC inhibitor dasatinib induced marked tumour regression in one patient whose disease was refractory to tyrosine kinase inhibitor treatment.
- The study’s abstract reports one treated patient, and gives no cohort size, response rate, duration of response or survival figure. The commentary’s published summary reports no data of its own.
Dual activation, with the SHC1 half signalling independently of the kinase domain
The EGFR-SHC1 fusion protein consists of an N-terminal EGFR portion and a C-terminal SHC1 portion. Zheng and colleagues report that it activates two things at once: the EGFR kinase domain, and SRC-mediated phosphorylation of the SHC1 fusion partner. Together these drive ERK and AKT pathway activation, and tumorigenesis, independently of kinase-domain inhibition, so blocking that domain alone leaves the tumour with a working signal.
The authors describe this as a kinase-independent bypass mechanism, established through structural modelling together with mutagenesis directed at specific domains. In this fusion the scaffold protein actively drives tumorigenesis, which they present as a cooperative oncogenesis between kinases and scaffold proteins.
Tumour regression in a single refractory patient on afatinib with dasatinib
The therapeutic implication the authors draw is to block both routes. A patient with NSCLC carrying EGFR-SHC1, refractory to tyrosine kinase inhibitor treatment, received afatinib, an EGFR inhibitor, with dasatinib, a SRC inhibitor. The authors report marked tumour regression.
That is one patient, and the study’s abstract reports no cohort, no response rate, no duration of response and no survival figure. The abstract states that the mechanism was shown in the preclinical and clinical settings, and this single case is the clinical evidence it presents.
Ultrarare fusions read as a route to new mechanisms and new treatment strategies
Le and Wolf read the finding as part of a pattern:
“Beyond established rare fusions, such as ALK and ROS1, emerging ultrarare fusions involving receptor tyrosine kinases or their ligands, including EGFR-SHC1, further guide us to uncover novel mechanisms of oncogenic activation and corresponding treatment strategies.”Le and Wolf, Cancer Discovery (2026)
They close on the collective effect, describing rare and ultrarare genomic events as moving precision oncology toward an increasingly individualised era of what they call ultraprecision cancer therapy. Neither the commentary’s summary nor the study’s abstract addresses how a fusion this rare would be identified in the first place.
Sources
- Cancer Discovery. Rare Fusions, Real Targets: Ultraprecision Oncology in Lung Cancer (2026-08-03). doi.org
Featuring Lung Summit faculty
This study was co-authored by Lung Summit faculty Xiuning Le.
This article was produced independently by the Lung Summit editorial team, without industry funding or input.
