ALK inhibitor–induced transformation of ALK fusion–positive lung adenocarcinoma to large cell neuroendocrine carcinoma

Cancer research · NSCLC · ALK · TP53

Sequential ALK‑TKI therapy (alectinib followed by lorlatinib) can drive histologic transformation from ALK‑positive lung adenocarcinoma to large cell neuroendocrine carcinoma (LCNEC), representing a novel mechanism of acquired resistance and highlighting the need to re‑biopsy and consider combinatorial immunotherapy, anti‑angiogenic, and chemotherapeutic strategies.

The transformation of lung adenocarcinoma into large cell neuroendocrine carcinoma (LCNEC) in terms of genotype and histology has been described as a mechanism of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‑TKI). However, this phenomenon is exceedingly rare in anaplastic lymphoma kinase (ALK)-positive lung adenocarcinoma. Here, we report a case of an ALK-positive lung adenocarcinoma patient who developed resistance following sequential treatment with the ALK‑TKI alectinib and lorlatinib, accompanied by histological transformation to LCNEC and concurrent genetic alterations including TP53 deletion, CDKN2A deletion, and MYC amplification. This case expands the spectrum of ALK‑TKI resistance mechanisms and highlights the potential value of exploring combinatorial approaches incorporating immunotherapy, antiangiogenic therapy, and chemotherapy for the management of such cases.

LCNEC transformation is a rare but clinically significant resistance mechanism to ALK‑TKIs, underscoring the importance of repeat biopsies on progression, the role of genomic profiling to anticipate lineage plasticity, and the potential benefit of adding immunotherapy and anti‑angiogenic agents to standard chemotherapeutic regimens in this subset of patients.

Evidence level: Sejtvonalas. Laboratóriumi sejtekben vizsgálták.

Original source

Related signals