Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer

Abstract

Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre- and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation.

Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors by Transformation to Small Cell Lung Cancer in an EGFR-mutant Patient

“…In the current case, it was nearly 16 months to second progression. Acquired resistance is mostly seen after 9 to 14 months of EGFR-TKI therapy (8). Similarly, in the present case, tumor progression occurred in the 13th month of erlotinib therapy.…”

“…In this instance, some specific genomic changes may have a role in SCLC transformation. In a patient with EGFR mutation, while liver metastasis showing SCLC phenotype had PTEN M2641, metastasis of adenocarcinoma phenotype didn't have this mutation (8). Sequist et al (18) reported a PI3K-AKT mutation with SCLC transformation, but a presence of only 5% of NSCLC cases.…”

“…However, acquired or secondary resistance to EGFR-TKIs is inevitable. Some alternative treatment options are currently available, depending on the resistance mechanisms (8). But the main dilemma lies in how to assess in which patient EGFR-TKI resistance may develop and for which patient to do a re-biopsy.…”

“…The coexistence of a T790M mutation with exon 19 deletion, BIM deletion polymorphism, and mesenchymal-epithelial transition (MET) amplification, are the pathways most suspected in primary resistance (7). EGFR T790M substitution, MET and ERBB2 gene amplification, overexpression of hepatocyte growth factor, down regulation of phosphatase and tensin homolog (PTEN) and transformation to SCLC are well-defined pathways of acquired resistance usually seen between months of 9 and 14 of EGFR-TKI treatment (8). In this instance afatinib and dacomitinib, second generation EGFR-TKIs, which bind irreversibly to EGFR receptors, may be considered as targeted therapy for patients who have resistance to first-line EGFR-TKIs (9,10).…”

Small Cell Transformation and T790M Mutation as Coresistance Mechanisms for First-line Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) Therapy Failure

“…Such findings support the concept of a reciprocal relationship between SCLC transformation and T790M mutation. 4 So far, there has been only one case report on the presence of T790M mutation in the primary lung adenocarcinoma that had transformed to SCLC. 5 Because adenocarcinoma and SCLC originate from the same stem cell, such rare transformation that preserves the EGFR TKI resistance property of adenocarcinoma is possible.…”