Clinical specimen tumor-TME acquired resistance

Project Summary/Abstract: The goal of this translational Project within BAATAAR-UP is to characterize the
mechanisms of, and therapeutically counteract, acquired resistance to molecular therapies in non-small cell lung
cancer (NSCLC) by delineating the tumor-tumor microenvironment (TME) ecosystem and its plasticity during
treatment. Acquired resistance (AR) is defined as tumor progression that occurs during active therapy and after
an initial therapy response. The overarching hypothesis is that AR can be therapeutically counteracted by
defining the cellular and signaling networks allowing tumors to survive and grow during therapy. The use of
molecularly targeted therapies that inhibit oncogenic driver alterations such as mutant EGFR and KRAS and
block immunosuppressive checkpoints such as PD1/L1 is improving outcomes for patients with aggressive
tumors including NSCLC, which nonetheless remains the leading cause of cancer mortality. Despite profound
progress, a major challenge to transforming NSCLC into a chronic or curable cancer is AR that enables lethal
tumor progression in patients. Understanding the mechanisms driving AR is essential to develop strategies to
counteract it and induce sustained anti-tumor responses to improve patient survival. Critical knowledge gaps are
whether and how tumor cell/TME cell interactions and spatial relationships promote AR. Another aspect of the
evolution of AR that is poorly defined is the basis of the incomplete response and residual disease that is typical
during therapy. This residual disease contains drug tolerant cancer cells and interactive TME cells that evolve
together to promote the aggressive transition into AR. Defining how this transition occurs could provide strategies
to thwart it. Our work accomplished during the prior U54 funding period showed that oncogene-driven NSCLCs
contain a rich cellular ecosystem that evolves during molecular treatments (e.g., EGFR, ALK, and RAS pathway
targeted agents). We discovered heterogeneity and plasticity in tumor cells and TME cells, including immune
and non-immune cell types, and spatial relationships at different clinical treatment states including at AR that we
hypothesize contribute collectively to AR. These include bi-directional interactions between tumor macrophages
and cancer cells and tumor fibroblasts and cancer cells via discrete signaling circuits that promote cancer cell
survival and remodel the TME into a more pro-tumor phenotype at AR. Examples include cytokine (CSF1, TNFa,
IL1b), and CD47 signaling between tumor macrophages and cancer cells and macrophage migration inhibitory
factor (MIF)-CD74/CD44 and extracellular matrix (ECM)/integrin signaling between tumor fibroblasts and cancer
cells at AR. Our goal is to define and therapeutically target these, and additional, cancer cell and TME cell
networks to therapeutically thwart AR. We focus on clinically important and prevalent NSCLC subtypes defined
by oncogenic mutant EGFR and KRAS and current clinical targeted inhibitors against these major oncogenic
drivers. Two Specific Aims are proposed. Our work will highlight mechanisms driving AR across the tumor-TME
continuum in EGFR- and KRAS-driven NSCLCs and identify counteracting therapeutic strategies for translation.

Grant Number: 5U54CA224081-08
NIH Institute/Center: NIH
Principal Investigator: Trever Bivona