Our comprehensive preclinical studies demonstrated the effectiveness of targeting DNA damage response (DDR) proteins like CHK1 and WEE1 inhibition in SCLC which has supported clinical testing of these inhibitors in SCLC patients. Additional preclinical data explored potential combinations of CHK1 inhibitor and chemotherapy and has identified MYC as a predictive biomarker of response to CHK1 inhibition in SCLC (Sen et al, 2017a). We established AKT/mTOR signaling as a mechanism of innate and acquired resistance to WEE1 inhibition in SCLC.

Current projects in the lab include: (1) validating the effectiveness of additional DDR proteins like ATR, ATM and DNAPKCs as a tractable SCLC target; (2) identifying mechanisms of resistance to DDR inhibition and exploring potential combination treatments to over resistance; and (3) discovery of SCLC subsets defined by the transcriptional signature that predicts improved responses to DDR targeted drugs. We are currently working other institution and industry partners to design biomarker-driven DDR inhibitor trials for SCLC.

Preliminary data from our group and others suggests that SCLCs evade anti-tumor immunity through repressing major histocompatibility complex class I (MHC class I) expression and antigen presentation. Recently published work suggested that polycomb repressive complex 2 (PRC2) transcriptionally silences the MHC Class I in multiple cancers. We demonstrated that, in SCLC, targeting epigenetic modifiers, like histone demethylase LSD1 restores MHC1 expression and thus anti-tumor immunity. One vital unanswered question is how the immune milieu and microenvironment differ between SCLC subtypes and whether there are any subtype specific effects of the epigenetic modifier targeting in SCLC.

Current projects in the lab include (1) discovering the epigenetic, transcriptional, and immune microenvironmental changes in clinical samples from patients with SCLC; (2) determine the strategy of reactivation of antigen presentation to overcome immune checkpoint blockade resistance in SCLC.

New therapeutic strategies are urgently needed to improve outcomes for patients with STK11/KEAP1 co-mutant non-small cell lung cancer (NSCLC). Concurrent STK11/KEAP1 loss-of-function (LOF) predicts poor (median overall survival of only 7.3 months) prognosis in NSCLC; compared to wildtype or single mutants.  STK11/KEAP1 LOF mutations dramatically enhance cell proliferation, invasive potential in vitro, and tumor growth in xenograft lung cancer models. Furthermore, NSCLC cell lines harboring single or co-mutation of STK11 and KEAP1, showed enrichment of pathways suppressing ferroptosis, and co-mutant cells were resistant to ferroptosis-mediated death. CRISPR/Cas9-based screening of these cells identified synthetic lethal interactions specific to the co-mutant state, including multiple regulators of ferroptosis. Our data suggest that isolated STK11 or KEAP1 mutations uniquely support global metabolic rewiring, ferroptosis evasion and provide multimodal ferroptosis protection in co-mutant models.

Current projects include (1) deeper biological understanding of the aggressive co-mutant subsets of KRAS-mutant NSCLC; (2) establish ferroptosis as a therapeutic vulnerability in STK11/KEAP1 co-mutant KRAS-mutant NSCLC; (3) develop novel therapies for STK11/KEAP1 co-mutant KRAS-mutant NSCLC.

Lineage plasticity (LP) is the ability of a tumor to transform from one histologic morphology to another and comprises a central mechanism of acquired resistance. LP was first recognized when an EGFR-mutant LUAD transformed to an aggressive neuroendocrine (NE) carcinoma resembling SCLC. The same phenomenon of NE transformation has been subsequently reported in the context of multiple other oncogenic driver mutations in LUAD, and in multiple other tumor types, including breast and prostate adenocarcinomas. We have previously observed that NE transformation in LUAD (with or without EGFR mutation) enhances therapeutic resistance and metastatic potential. Derivative therapy-resistant transformed-SCLC (T-SCLC) tumors typically exhibit molecular and clinical characteristics similar to de novo SCLC, including a high prevalence of RB1 and TP53 alterations, expression of NE markers, and transient response to platinum-based chemotherapy. Our data suggest that RB1 and TP53 mutations are required, but not sufficient, for NE-transformation. Understanding these mechanisms and developing effective strategies to prevent histologic transformation in lung cancer are critically important.

The focus of our lab is to systematically uncover core mechanisms facilitating lung cancer plasticity in a driver mutation agnostic manner. We are applying single cell technologies and gene editing techniques in clinical tumor samples patient-derived models during therapy to discover the cell states of tumor cells during LP. We aim to identify tumor cell intrinsic and immune microenvironmental factors contributing to LP. Our long-term goal is to develop therapies to reverse or prevent LP as a mechanism of acquired resistance.