Non-small cell lung cancer-small cell lung cancer transformation as mechanism of resistance to tyrosine kinase inhibitors in lung cancer

Abstract

Mutated or rearranged driver kinases in non-small cell lung cancer (NSCLC) cells are clinically amenable to treatment with tyrosine kinase inhibitors (TKIs) resulting in prolonged survival and significant benefit compared to cytotoxic chemotherapy. The most frequent genomic alterations are observed for epidermal growth factor receptor and anaplastic lymphoma kinase, which can be blocked by a range of specific TKIs in sequence. In clinics, resistance to TKIs emerges after approximately one year and comprises secondary mutations of the kinases (on-target) or alternative pathways circumventing the original kinase (off-target) alterations. A special feature of NSCLC is the occurrence of histological transformation to small cell lung cancer (SCLC) in up to 14% of cases, which, in general, is accompanied by resistance to the original TKIs. SCLC transformed tumors may be treated with the classical platinum/etoposide regimen but thus far there are no definitive guidelines. Four transformed pleural SCLC lines in our lab indicate the presence of a gradual NSCLC-SCLC shift with overlapping drug sensitivities. In conclusion, the treatment of NSCLC-SCLC transformed cancer cells would need a better chemosensitivity assessment using functional genomics to guide further therapy.

Keywords: Lung cancer; chemotherapy; drug resistance; epidermal growth factor receptor; non-small cell lung cancer; small cell lung cancer; transformation; tyrosine kinase inhibitor.

Figure 1

This scheme represents the sequence of therapeutic regimens in EGFR-mutated NSCLC. Tumors are treated with first-line agents erlotinib, gefitinib, or afatinib. Alternatively, the second-line osimertinib is applied directly or as actual second-line therapy. C797S may appear as further mutation of EGFR followed by progress and eventually by rescue chemotherapy. First-line osimertinib is rendered inactive by loss of T790M and the patients may be further treated by targeted agents against alternative pathway modulators and, upon progress, by rescue chemotherapy. Switch to a SCLC histotype may occur from both branches of therapy and result in cancer resistance and progress. SCLC: small cell lung cancer; EGFR: epidermal growth factor receptor; NSCLC: non-small cell lung cancer

Figure 2

NSCLC-SCLC transformed pleural cell lines display either a phenotype still similar to a typical adenocarcinoma as in the case of BH15 (A) or a classical SCLC phenotype as in the case of BH20 (B). Both cell lines express SCLC markers. NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer