Cancer Plasticity Talk - examining histological transition in lung cancer

review of histological transformation (gardner et al.)

1. 2024 MSKCC Hematology-Oncology Cancer Biology Series: Phenotypic Plasticity Guest discussant: Harold Varmus, PhD Presenter: Samuel Taylor, MD, PhD

2. Harold Varmus, MD 12/20/2024 2 Professor of Medicine, Meyer Cancer Center, Weill Cornell Medicine Former Director of the National Cancer Institute (2010–2015) and National Institutes of Health (1993–1999) President and CEO of MSKCC (2000-2010) Co-recipient of the 1989 Nobel Prize in Physiology or Medicine for discoveries concerning the genetic basis of cancer Established PubMed Central and PLOS MSKCC Cancer Biology Series: Plasticity in Cancer

3. What is Cellular Plasticity? 12/20/2024 3 The ability of cells to acquire new phenotypes via differentiation or dedifferentiation Normal Contexts: Development (e.g., embryogenesis) Tissue regeneration (e.g., wound healing, alveolar injury) MSKCC Cancer Biology Series: Plasticity in Cancer

4. High-Plasticity Cell States (HPCSs) 12/20/2024 4 Characteristics: Cancer cell states with maximal phenotypic flexibility Central hubs for cell state transitions Drivers of heterogeneity and therapy resistance Cancer Context: Initiation (e.g. CRC from IBD) Progression (e.g. LUAD heterogeneity) Metastasis (e.g., EMT) Therapy resistance (e.g., EGFR independence in LUAD) MSKCC Cancer Biology Series: Plasticity in Cancer

5. Mechanisms Underlying Plasticity (there are many) 12/20/2024 5 MSKCC Cancer Biology Series: Plasticity in Cancer

6. Histologic Transformation 12/20/2024 6 EGFRmut lung adenocarcinoma (LUAD) + TKI  small cell lung cancer (SCLC) prostate adenocarcinoma + ADT  neuroendocrine prostate cancer (NEPC) MSKCC Cancer Biology Series: Plasticity in Cancer PMID: 36583000

7. Primary LUAD and SCLC Have Distinct Lineages and Genotypes 12/20/2024 7 Lineage: LUAD: surfactant-producing AT2 cells SCLC: pulmonary neuroendocrine cells (PNEC) Genotype: LUAD: MAPK activation driver SCLC: RB and TP53 loss, high mutation burden, unknown driver MSKCC Cancer Biology Series: Plasticity in Cancer

8. Clinical Impact of Histologic Transformation (HT) 12/20/2024 8 Lung Cancer (LUAD to SCLC): occurs in 3-10% of EGFR-mutant LUAD cases treated with EGFR TKIs Median time to transformation: 17.8 months after EGFR TKI therapy Median survival after transformation: 6.2 months, compared to 31.5 months for patients who do not undergo HT Increased resistance to EGFR TKIs and increased metastatic burden Prostate Cancer (Adenocarcinoma to NEPC): ~17-30% of castration-resistant prostate cancer cases. rapid progression, therapy resistance, and poor prognosis, with median survival of ~10 months. MSKCC Cancer Biology Series: Plasticity in Cancer

9. Lineage-specific intolerance to oncogenic drivers restricts histological transformation Eric E. Gardner, Ethan M. Earlie, Kate Li1, Jerin Thomas, Melissa J. Hubisz , Benjamin D. Stein, Chen Zhang, Lewis C. Cantley, Ashley M. Laughney , Harold Varmus 12/20/2024 9 MSKCC Cancer Biology Series: Plasticity in Cancer

10. Introduction 12/20/2024 10 Questions this study aims to answer: How does an adenocarcinoma transform into a high-grade neuroendocrine cancer? what are the intermediate steps in HT? what is the oncogenic driver program of the pulmonary neuroendocrine lineage? MSKCC Cancer Biology Series: Plasticity in Cancer

11. 12/20/2024 11 MSKCC Cancer Biology Series: Plasticity in Cancer Cell of Origin Control: Genes under control of Cre: LSL- Myc LSL-tdTom (for reporting) Tumor suppressor deletions ( floxed Rb1, Tp53) intratracheal adenoviral infection w/ Cre under lineage-specific promoters: - SPC (AT2 lineage) - CGRP (PNEC lineage) ERPMT Mouse Model Setup

12. 12/20/2024 12 MSKCC Cancer Biology Series: Plasticity in Cancer ERPMT Mouse Model Setup Oncogene Activation: DOX-dependent expression of oncogenic EGFR L858R, allowing 6 different model states: No virus: On DOX: EGFR active in both AT2 and PNEC lineages Off DOX: no trans genes active AT2-targeted virus: On DOX: MYC, tdTom, EGFR active ; RB1, TP53 deleted Off DOX: MYC, tdTom active ; RB1, TP53 deleted PNEC-targeted virus: On DOX: MYC, tdTom, EGFR active ; RB1, TP53 deleted Off DOX: MYC, tdTom active ; RB1, TP53 deleted

13. 12/20/2024 13 MSKCC Cancer Biology Series: Plasticity in Cancer A GEMM model to generate distinct histologic subtypes of lung cancer AT2 Lineage, Cre+: On DOX: LUAD develops (aggressive adenocarcinoma) Off DOX: Mice remain healthy. PNEC Lineage, Cre+: On DOX: Mice remain healthy. Off DOX: Aggressive SCLC develops. Next: Can we use this to turn LUAD tumors into SCLC?

14. 12/20/2024 14 MSKCC Cancer Biology Series: Plasticity in Cancer Tracing LUAD to SCLC Transition in the ERPMT Model All: ERPMT mouse

15. 12/20/2024 15 MSKCC Cancer Biology Series: Plasticity in Cancer An Undifferentiated Cell Lies at the Bottleneck All: ERPMT mouse

16. 12/20/2024 16 MSKCC Cancer Biology Series: Plasticity in Cancer An Undifferentiated Cell Lies at the Bottleneck All: ERPMT mouse

17. 12/20/2024 17 MSKCC Cancer Biology Series: Plasticity in Cancer AT2, but not PNEC, are refractory to transformation by Myc *Rb1, Trp53 WT mice * *

18. 12/20/2024 18 MSKCC Cancer Biology Series: Plasticity in Cancer Pten loss facilitates Myc -driven transformation (to LUAD) in AT2 cells All: Rb1, Trp53 WT mice

19. 12/20/2024 19 MSKCC Cancer Biology Series: Plasticity in Cancer

20. 12/20/2024 20 MSKCC Cancer Biology Series: Plasticity in Cancer Myc overexpression and Rb1 loss are both required for efficient histologic transformation (HT) from LUAD to SCLC

21. 12/20/2024 21 MSKCC Cancer Biology Series: Plasticity in Cancer Myc overexpression and Rb1 loss are both required for efficient histologic transformation (HT) from LUAD to SCLC

22. 12/20/2024 22 MSKCC Cancer Biology Series: Plasticity in Cancer Conclusions The AT2 cell is highly refractory to transformation by oncogenic Myc Intolerance of AT2 cells to Myc can be relieved through activation of the Akt signaling pathway the full conversion to a Myc -driven, high-grade neuroendocrine cancer requires the additional loss of Rb1

23. 12/20/2024 23 MSKCC Cancer Biology Series: Plasticity in Cancer Clinical Impact HT as a mechanism of therapy resistance in LUAD treated with EGFR inhibitors and prostate cancer treated with androgen receptor inhibitors. Potential biomarkers for monitoring HT risk: PI3K mutations, MYC activation signatures. Therapeutic opportunities: Targeting MYC-driven transcription or PI3K/AKT signaling pathways

24. Plasticity as a Therapeutic Target 12/20/2024 24 Challenges: Targeting plastic cells without affecting normal tissue regeneration Identifying actionable vulnerabilities specific to high-plasticity states Promising Strategies: YAP/TAZ suppression in CRC and LUAD EZH2 inhibitors in prostate cancer MSKCC Cancer Biology Series: Plasticity in Cancer PMID: 31601994

25. 12/20/2024 25 MSKCC Cancer Biology Series: Plasticity in Cancer Discussion How can we leverage the identification of "bottleneck" states during HT to develop therapies that prevent or reverse transformation? What are the challenges and opportunities in using circulating tumor DNA ( ctDNA ) to monitor and predict HT in clinical settings? W hat should we be targeting in the MRD of a patient that is poised to transform? Are Myc and PI3K directed therapies useful in the context of histologic transformation and/or are there promising targets? How do these findings apply to LUAD-> SqCLC ? Is the transformation pathway distinct or reliant on different drivers?