Deterministic reprogramming and signaling activation following targeted therapy in non-small cell lung cancer driven by mutations or oncogenic fusions

ABSTRACT

Introduction

Targeted therapy is used to treat lung adenocarcinoma caused by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain and rare subtypes (<5%) of non-small cell lung cancer. These subtypes include fusion oncoproteins like anaplastic lymphoma kinase (ALK), ROS1, rearranged during transfection (RET), and other receptor tyrosine kinases (RTKs). The use of diverse selective oral inhibitors, including those targeting rat sarcoma viral oncogene homolog (KRAS) mutations, has significantly improved clinical responses, extending progression-free and overall survival.

Areas Covered

Resistance remains a critical issue in lung adenocarcinoma, notably in EGFR mutant, echinoderm microtubule associated protein-like 4 (EML4)-ALK fusion, and KRAS mutant tumors, often associated with epithelial-to-mesenchymal transition (EMT).

Expert Opinion

Despite advancements in next generation EGFR inhibitors and EML4-ALK therapies with enhanced brain penetrance and identifying resistance mutations, overcoming resistance has not been abated. Various strategies are being explored to overcome this issue to achieve prolonged cancer remission and delay resistance. Targeting yes-associated protein (YAP) and the mechanisms associated with YAP activation through Hippo-dependent or independent pathways, is desirable. Additionally, the exploration of liquid-liquid phase separation in fusion oncoproteins forming condensates in the cytoplasm for oncogenic signaling is a promising field for the development of new treatments.

KEYWORDS:

• EGFR mutations
• EML4-ALK fusions
• KRAS mutations
• liquid-like condensates
• lung adenocarcinoma
• N-terminal fusion partners
• yes-associated protein (YAP)

Article highlights

• Targeted therapies improve progression free survival and overall survival in many sub-classes of non-small cell lung cancer (NSCLC) identifiable by tractable genetic alterations, EGFR mutations, or an assortment of fusion oncoproteins, mostly ALK, ROS, RET, and TRKs, which are relatively less recognized and uncommon.

• Stand-alone targeted therapy inevitably results in clinical progression after a period of remission (usually 1-3 years, sometimes less than 1 year in KRAS exon 2 p. G12C mutant non-small cell lung cancer), despite the rapid evolution of more potent KRAS exon 2 p. G12C covalent inhibitors.

• Compelling evidence indicates that epithelial-to-mesenchymal transition occurs early in lung cancer cells upon treatment onset, leading to activation of yes-associated protein (YAP) and downstream effectors, including MRAS, clearly highlighted in KRAS exon 2 p. G12C mutant lung cancers.

• Most fusion oncoproteins lack the transmembrane domain form liquid-like condensates driven by their N-terminal fusion partners that are critical for organizational hubs and oncogenic signaling, mainly promoting the mitogen-activated protein kinase (MAPK) pathway.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

R Rosell conceptualized and drafted the manuscript. R Rosell, C Pedraz-Valdunciel, A Jain, C Shivamallu and A Aguilar revised the manuscript. R Rosell, A Jain and C Pedraz-Valdunciel drafted the figures. R Rosell, A Jain and C Pedraz-Valdunciel revised the figures. All authors have read and agreed to the published version of the manuscript.

Additional information

Funding

This work is in memory of the generous support provided by the late Julian Santamaría Valiño to the IOR Foundation.