Molecular Characterization of Lineage Plasticity

2021

EGFR Resisters / LUNGevity Research Award

Helena Yu, MD

Memorial Sloan Kettering Cancer Center

New York

As a mechanism of resistance to EGFR inhibitors, cancers can change histology from adenocarcinoma to small cell or squamous cell lung cancer. Once this happens, EGFR inhibitors are no longer effective treatment; there are no strategies currently available to prevent or reverse transformation after it has occurred. Dr. Yu will use advanced molecular techniques to identify genetic changes that contribute to transformation. Understanding these genetic changes will identify biomarkers that can be utilized to develop treatments to prevent and reverse transformation.

Research Summary

Metastatic EGFR-mutant lung cancer remains an incurable disease despite significant advances in cancer therapeutics. With better EGFR inhibitors, we have identified new mechanisms of resistance that are independent of EGFR signaling, notably small cell and squamous cell histologic transformation. Targeted therapies are ineffective and survival is shortened once transformation has occurred, and no strategies are available to prevent or reverse transformation after it has occurred.

Mutations in EGFR, TP53, and RB1 are associated with transformation, but additional genetic or epigenetic changes must occur for transformation to happen. We will use advanced molecular techniques to identify the mutations and cell signaling pathways that drive transformation in order to identify biomarkers that can be utilized to develop treatments to prevent and reverse transformation. Treatments will then be validated in our unique pre-clinical models which can be rapidly translated into clinical trials, providing treatments for these aggressive cancers.

Technical Abstract

EGFR-mutant lung cancers (LC) serve as the prototype oncogene-driven cancer and mechanisms of resistance to EGFR therapy are well-established. Selective pressure of EGFR inhibitors can induce lineage plasticity to escape oncogene-dependence. While we have shown EGFR/TP53/RB1-mutations are necessary but insufficient to induce small cell transformation, no other genomic signatures and transcriptomic/epigenomic effectors that induce transformation have been identified.

Using parallel exome sequencing, bulk RNA sequencing, and bisulfite sequencing, we will characterize the biomarkers of transformation in EGFR/TP53/RB1-mutant LC and mixed adenocarcinoma/squamous cell tumors. We will also utilize single-cell RNA sequencing to identify the transcriptional changes associated with transformation and to identify distinct cell types within a heterogenous tumor. We will reconstruct a phenotypic landscape to identify subclones in a transitional state between histologies. The information obtained from these studies will nominate novel biomarkers of lineage plasticity that will be validated and proposed for study in clinical trials.

Key words

Acquired resistance

Adenocarcinoma

Biomarker or biomarker testing

Epidermal growth factor receptor (EGFR)

Metastatic

Molecular profile or molecular testing

Mutation profile

Non-small cell lung cancer (NSCLC)

Small cell lung cancer (SCLC)

Squamous cell lung cancer

Stage III