Targeting cancer stem cell pathways for lung cancer therapy

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Abstract

Purpose of review

The unique properties of cancer stem cells (CSCs) make lung cancer untargetable for quite an extended period. The functional mechanism of this cell type has been illustrated step by step. However, the outcomes of lung cancer patients are still lower than expected clinically. The attempts made by scientists to make challenge history against stemness maintenance of lung cancer cells and their druggable targets are worth elucidating.

Recent findings

Many agents, including the Bispecific T-cell engager (BiTE) and AMG 119 targeting DLL3-positive cells, are a tremendous breakthrough in the preclinical and clinical treatment of SCLC. More studies focus on targeting CSCs to overcome TKI resistance in NSCLC. The combo targeting of CSC and the immune microenvironment can favor the treatment of lung cancer patients.

Summary

The current review elucidates the characteristics and related regulating pathways of lung CSCs from essential to preclinical research. We retrospectively introduce an update on the clinical development of therapeutics targeting CSC-associated developmental signaling pathways and discuss the opportunities to target CSC–immune interactions in lung cancer.

Related collections

Most cited references 72

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Targeting signalling pathways and the immune microenvironment of cancer stem cells — a clinical update

Joseph A. Clara, Cecilia Monge, Yingzi Yang … (2019)

Cancer stem cells (CSCs) have important roles in tumour development, relapse and metastasis; the intrinsic self-renewal characteristics and tumorigenic properties of these cells provide them with unique capabilities to resist diverse forms of anticancer therapy, seed recurrent tumours, and disseminate to and colonize distant tissues. The findings of several studies indicate that CSCs originate from non-malignant stem or progenitor cells. Accordingly, inhibition of developmental signalling pathways that are crucial for stem and progenitor cell homeostasis and function, such as the Notch, WNT, Hedgehog and Hippo signalling cascades, continues to be pursued across multiple cancer types as a strategy for targeting the CSCs hypothesized to drive cancer progression - with some success in certain malignancies. In addition, with the renaissance of anticancer immunotherapy, a better understanding of the interplay between CSCs and the tumour immune microenvironment might be the key to unlocking a new era of oncological treatments associated with a reduced propensity for the development of resistance and with enhanced antimetastatic activity, thus ultimately resulting in improved patient outcomes. Herein, we provide an update on the progress to date in the clinical development of therapeutics targeting the Notch, WNT, Hedgehog and Hippo pathways. We also discuss the interactions between CSCs and the immune system, including the potential immunological effects of agents targeting CSC-associated developmental signalling pathways, and provide an overview of the emerging approaches to CSC-targeted immunotherapy.

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MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by Reprogramming Neuroendocrine Fate

Abbie Ireland, Alexi Micinski, David Kastner … (2020)

Small cell lung cancer (SCLC) is a neuroendocrine tumor treated clinically as a single disease with poor outcomes. Distinct SCLC molecular subtypes have been defined based on expression of ASCL1, NEUROD1, POU2F3, or YAP1. Here, we use mouse and human models with a time-series single-cell transcriptome analysis to reveal that MYC drives dynamic evolution of SCLC subtypes. In neuroendocrine cells, MYC activates Notch to dedifferentiate tumor cells, promoting a temporal shift in SCLC from ASCL1+ to NEUROD1+ to YAP1+ states. MYC alternatively promotes POU2F3+ tumors from a distinct cell type. Human SCLC exhibits intratumoral subtype heterogeneity, suggesting that this dynamic evolution occurs in patient tumors. These findings suggest that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype.

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Author and article information

Journal

Title: Current Opinion in Oncology

Publisher: Ovid Technologies (Wolters Kluwer Health)

ISSN (Print): 1040-8746

ISSN (Electronic): 1531-703X

Publication date Created: 2023

Publication date (Print): January 2023

Publication date (Electronic): November 2 2022

Volume: 35

Issue: 1

Pages: 78-85

Article

DOI: 10.1097/CCO.0000000000000912

PubMed ID: 36475460

SO-VID: a2bb0346-6718-42b1-9059-caab7f970d21

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