SCLC subtypes show potential for more personalised therapeutic approaches

Lung cancer

By Michael Woodhead

26 May 2022

Small cell lung cancer (SCLC) can be divided into three specific molecular subgroups in terms of clinical behaviour, European researchers have shown.

Differential expression of the subtype-specific proteins ASCL1, NEUROD1, and POU2F3 in tumour tissue defines biologically distinct SCLC subtypes that also have different disease outcomes in response to drug therapies , according to a multicentre study led by a team from Medical University of Vienna, Austria.

Their findings, published in the Journal of Pathology are based on immunohistochemistry (IHC) analysis of surgically resected tumour samples from 386 patients with SCLC, followed by investigation of subtype-specific therapeutic vulnerabilities in a proteomics study combined with in vitro cytotoxicity assays in a large panel of human SCLC cell lines.

The analysis found that in addition to the classic SCLC-A (ASCL1-dominant) subtype there were variations such as SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant) and SCLC-P (POU2F3-dominant) types of SCLC and also a quadruple-negative SCLC subtype (SCLC-QN).

The highest overall survival rates were associated with non-neuroendocrine subtypes (SCLC-P and SCLC-QN) and the lowest with neuroendocrine subtypes (SCLC-A, SCLC-N, SCLC-AN).

High ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model.

The researchers noted that some subtypes respond differently to chemotherapeutics and targeted drugs.  High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard-of-care chemotherapeutics, respectively.

Specific correlation patterns were also found between the efficacy of targeted agents and subtype-specific protein abundances.

These findings opened up possibilities for personalised treatment for SCLC, the researchers said.

“In contrast to the increasingly personalised approaches observed in non-small cell lung cancer, SCLC is still considered to be a homogeneous clinical picture and is treated in a standardised way both in hospitals and laboratories,” said lead author Dr Zsolt Megyesfalvi from the Translational Thoracic Oncology Lab at the Medical University of Vienna’s Department of Thoracic Surgery.

“We are now showing that differential expression of key transcriptional regulators clearly distinguishes five major SCLC subtypes.”

Study leader Dr Balazs Döme, Head of the Translational Thoracic Oncology programme at the Medical University of Vienna said the results from in vitro experiments with tumour cells had revealed the diversity of SCLC and would help to facilitate the implementation of subtype-specific personalised approaches to treatment and follow-up strategies in this disease.

“Notably, high POU2F3 expression, which is associated with better survival, correlated with sensitivity to standard chemotherapeutics. In contrast, high YAP1 protein expression correlated with poor response to chemotherapy. In addition, the abundance of subtype-defining proteins was also associated with the efficacy of certain targeted drugs such as CDK, AURK, and IGF-1R inhibitors.”

“Altogether, our results might help in the development of subtype-specific therapeutic approaches and follow-up strategies in this devastating disease,” the team concluded.

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