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Research
My laboratory studies tumorigenesis and resistance to targeted therapy in cancers that harbor rare oncogenic drivers (mainly gene fusions in solid tumors). A major focus of the lab is to study the biology of NTRK fusion-positive tumors and to unveil mechanisms of resistance to TRK inhibitors in these malignancies.
We identified both on-target and bypass mechanisms of resistance to TRK inhibition in multiple cancer types. In an initial study, published in Nature Medicine, we identified that alterations in the MAPK pathway could confer resistance to TRK inhibition in a series of gastrointestinal (GI) cancer patients progressing to first and/or next-generation TRK inhibitors. Specifically, we showed that six out of 8 GI tumors acquired alterations involving upstream non-TRK receptor kinases and downstream MAPK pathway members that converge in the activation of ERK signaling. Two patients were subsequently treated with tailored combinations of agents directed against these emerging alterations and achieved objective clinical responses. Together, our data provide the first evidence that a subset of TRK fusion-positive GI cancers will develop off-target resistance to TRK inhibition that may be successfully managed with tailored combinatorial therapies. More recently, we discovered that TRKA xDFG mutations can confer primary and acquired resistance to 2nd-generation TRK inhibitors in patients. These mutations also induce the mutant kinase to preferentially adopt the DFG-out conformation, thus sensitizing to type II TRK inhibitors. Consistently, treatment of these resistant tumors with cabozantinib, foretinib or ponatinib result in strong and durable tumor response in primary and isogenic cell models and in vivo in PDXs established from patient-derived resistant tumors (Cocco E et al., Cancer Discov 2021).
In addition, my laboratory is interested in evaluating the role that mutated epigenetic regulators have in the development of women cancers including breast cancer and gynecological malignancies.
We found that the PI3K pathway regulates estrogen receptor (ER)-dependent transcription in breast cancer through the phosphorylation of KMT2D by AKT and SGK1. This crosstalk is overall important in the context of Pi3Kα inhibition that results in the hyperactivation of the ER-dependent transcriptional program as an adaptive response used by tumor cells to escape therapeutic pressure. In another more recent study, by performing an epigenome CRISPR knock out screening, we identified ARID1A (a member of the SWI/SNF complex) as the top candidate whose loss determined resistance to the ER degrader fulvestrant. Mechanistically, ARID1A disruption in ER+ breast cancer cells led to widespread changes in chromatin accessibility converging on loss of activity of master transcription factors that regulate gene expression programs critical for luminal lineage identity. In another work, we characterized some mutations in the pioneer factor FOXA1 that were shown to be enriched in tumors from breast cancer patients who progressed to anti-hormonal therapy. We found that one group of mutants displayed increased chromatin binding at ER loci upon estrogen stimulation, and an enhanced ER-mediated transcription without changes in chromatin accessibility. In contrast, the SY242CS double mutant showed neomorphic properties that include the ability to open distinct chromatin regions and activate an alternative cistrome and transcriptome.
In an ongoing study, we aim to understand the mechanisms by which mutant histone genes mediate uterine and ovarian carcinosarcoma (CS) histogenesis and chemotherapy resistance. Alterations in these genes have been identified by our group in a recent genomic study in which we evaluated the genetic landscape of ~70 uterine and ovarian CS. Initial studies suggest that some of these mutations are involved in Epithelial-to-Mesenchymal Transition (EMT) in these tumors. However, the molecular mechanisms through which this process is regulated are not known. We will study in depth the phenotypical changes that the overexpression of these mutant histones induces in carcinoma cells and, more comprehensively, the effect that their overexpression has on global chromatin accessibility and gene expression.