Single‐cell transcriptomic analysis uncovers intratumoral heterogeneity and drug‐tolerant persister in <i>ALK</i>‐rearranged lung adenocarcinoma

Kwok, Hoi‐Hin; Li, Huiyu; Yang, Jiashuang; Deng, Jianghong; Lee, N.; Au, Wing‐Kuk; Sit, Alva K Y; Hsin, Michael K.Y.; Kwai-Yee, Stephanie; Cheung, Lydia W.T.; Girard, Luc; Fujimoto, Junya; Wistuba, Ignacio I.; Gao, Boning; Minna, John D.; Lam, David Chi‐Leung

doi:10.1002/cac2.12449

Cancer Communications

2023

DOI: 10.1002/cac2.12449

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Single‐cell transcriptomic analysis uncovers intratumoral heterogeneity and drug‐tolerant persister in ALK‐rearranged lung adenocarcinoma

Hoi‐Hin Kwok

Huiyu Li

Jiashuang Yang

et al.

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2024

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Cited by 3 publications

References 10 publications

(15 reference statements)

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scPharm: Identifying Pharmacological Subpopulations of Single Cells for Precision Medicine in Cancers

Tian,

Zheng,

Qiao

et al. 2024

Advanced Science

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Intratumour heterogeneity significantly hinders the efficacy of anticancer therapies. Compared with drug perturbation experiments, which yield pharmacological data at the bulk cell level, single‐cell RNA sequencing (scRNA‐seq) technology provides a means to capture molecular heterogeneity at single‐cell resolution. Here, scPharm is introduced, a computational framework that integrates pharmacological profiles with scRNA‐seq data to identify pharmacological subpopulations of cells within a tumour and prioritize tailored drugs. scPharm uses the normalized enrichment scores (NESs) determined from gene set enrichment analysis to assess the distribution of cell identity genes in drug response‐determined gene lists. Based on the strong correlation between the NES and drug response at single‐cell resolution, scPharm successfully identified the sensitive subpopulations in ER‐positive and HER2‐positive human breast cancer tissues, revealed dynamic changes in the resistant subpopulation of human PC9 cells treated with erlotinib, and expanded its ability to a mouse model. Its superior performance and computational efficiency are confirmed through comparative evaluations with other single‐cell prediction tools. Additionally, scPharm predicted combination drug strategies by gauging compensation or booster effects between drugs and evaluated drug toxicity in healthy cells in the tumour microenvironment. Overall, scPharm provides a novel approach for precision medicine in cancers by revealing therapeutic heterogeneity at single‐cell resolution.

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scPharm: Identifying Pharmacological Subpopulations of Single Cells for Precision Medicine in Cancers

Tian,

Zheng,

Qiao

et al. 2024

Advanced Science

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Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies

He,

Qiu,

Fan

et al. 2024

Sig Transduct Target Ther

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Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance. Among these, the drug tolerant persister (DTP) cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance. The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli, which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal, ultimately leading to treatment resistance and cancer recurrence. Therefore, targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients, although our current knowledge of these DTP cells in treatment resistance remains limited. In this review, we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells, investigate the potential drugs for DTP (including preclinical drugs, novel use for old drugs, and natural products) based on different medicine models, and discuss the necessity and feasibility of anti-DTP therapy, related application forms, and future issues that will need to be addressed to advance this emerging field towards clinical applications. Nonetheless, understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.

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Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient

Ge,

Dai,

Qiu

et al. 2024

Acta Pharmacol Sin

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Single‐cell transcriptomic analysis uncovers intratumoral heterogeneity and drug‐tolerant persister in ALK‐rearranged lung adenocarcinoma

Cited by 3 publications

References 10 publications

scPharm: Identifying Pharmacological Subpopulations of Single Cells for Precision Medicine in Cancers

scPharm: Identifying Pharmacological Subpopulations of Single Cells for Precision Medicine in Cancers

Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies

Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient

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