Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

Abstract

Somatic alterations in the epidermal growth factor receptor gene (EGFR) result in aberrant activation of kinase signaling and occur in ∼15% of non-small cell lung cancers (NSCLC). Patients diagnosed with EGFR-mutant NSCLC have good initial clinical response to EGFR tyrosine kinase inhibitors (EGFR TKIs), yet tumor recurrence is common and quick to develop. Mechanisms of acquired resistance to EGFR TKIs have been studied extensively over the past decade. Great progress has been made in understanding two major routes of therapeutic failure: additional genomic alterations in the EGFR gene and activation of alternative kinase signaling (so-called "bypass activation"). Several pharmacological agents aimed at overcoming these modes of EGFR TKI resistance are FDA-approved or under clinical development. Phenotypic transformation, a less common and less well understood mechanism of EGFR TKI resistance is yet to be addressed in the clinic. In the context of acquired EGFR TKI resistance, phenotypic transformation encompasses epithelial to mesenchymal transition (EMT), transformation of adenocarcinoma of the lung (LUAD) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). SCLC transformation, or neuroendocrine differentiation, has been linked to inactivation of TP53 and RB1 signaling. However, the exact mechanism that permits lineage switching needs further investigation. Recent reports indicate that LUAD and SCLC have a common cell of origin, and that trans-differentiation occurs under the right conditions. Options for therapeutic targeting of EGFR-mutant SCLC are limited currently to conventional genotoxic chemotherapy. Similarly, the basis of EMT-associated resistance is not clear. EMT is a complex process that can be characterized by a spectrum of intermediate states with diverse expression of epithelial and mesenchymal factors. In the context of acquired resistance to EGFR TKIs, EMT frequently co-occurs with bypass activation, making it challenging to determine the exact contribution of EMT to therapeutic failure. Reversibility of EMT-associated resistance points toward its epigenetic origin, with additional adjustments, such as genetic alterations and bypass activation, occurring later during disease progression. This review will discuss the mechanistic basis for EGFR TKI resistance linked to phenotypic transformation, as well as challenges and opportunities in addressing this type of targeted therapy resistance in EGFR-mutant NSCLC.

Clinical Impact of the Epithelial-Mesenchymal Transition in Lung Cancer as a Biomarker Assisting in Therapeutic Decisions

“…This complexity certainly contributes to slow down the implementation of EMT consideration in clinical routine. EMT programs may indeed be triggered by several factors, such as transforming growth factor-β (TGF-β) [Miyazono et al, 2018], fibroblast growth factor (FGF) [Katoh and Nakagama, 2014], epidermal growth factor (EGF) [Shaurova et al, 2020], Notch, or Wnt signaling pathways [Yuan et al, 2014;Patel et al, 2019]. Activated signaling pathways converge onto a set of transcription factors, such as Snail, ZEB, and Twist family [Zeisberg and Neilson, 2009].…”

Combination of tissue and liquid biopsy molecular profiling to detect transformation to small cell lung carcinoma during osimertinib treatment

“…Nevertheless, our results highlight the high intra-tumor heterogeneity and the acquisition of different molecular alterations that hinder EGFR TKI efficacy, as previously reported. 12 , 23 , 36 – 38 …”

The History and Mystery of Alveolar Epithelial Type II Cells: Focus on Their Physiologic and Pathologic Role in Lung

“…Furthermore, a reduced Wnt signaling in the COPD microenvironment has been associated with defective alveolar epithelial repair. It has also been suggested that this defective response is downstream to a shift in canonical to noncanonical Wnt signaling in the presence of toxic stimuli, such as cigarette smoke [ 67 , 71 , 72 , 73 , 74 ]. It still remains a question of debate whether Wnt signaling is associated with an aberrant or absent response by the Wnt-responsive progenitor ATII cell sub-lineage in the ATII cell population [ 71 ].…”