In the Goel laboratory, we study the cell cycle machinery and how it influences breast cancer biology in both cancer cells and stromal cells. We aim to leverage our discoveries to design new drug therapies for breast cancer.
Dysregulated cellular proliferation is a hallmark of cancer. In the majority of breast cancers, division of cancer cells is dependent on cyclin-dependent kinases 4 and 6 (CDK4/6), enzymes which promote the transition of a cell from the G1 phase of the cell cycle into the S phase. Recently, pharmacologic CDK4/6 inhibitors have become available and these agents have dramatically improved survival outcomes for many breast cancer patients.
Although CDK4/6 inhibitors were designed to inhibit cancer cell proliferation, it is clear that they do much more than this. For example, we have shown that CDK4/6 inhibitors can rewire kinase circuitry within breast cancer cells, providing a rationale for combining them with inhibitors of receptor tyrosine kinases (RTKs). We have also discovered that CDK4/6 inhibitors enhance anti-tumour immunity, a previously unappreciated mechanism for their activity.
In the Goel lab, we believe that it is critical to gain a deeper understanding on how CDK4/6 inhibitors exert their effects in breast cancer – not only on breast cancer cells, but also on immune cells and other stromal cell types. Only then we will be able to find ways to make these drugs even more effective and also develop strategies to overcome CDK4/6 inhibitor resistance.
Some of the key techniques we use in the lab include:
- Creation of novel, immune-competent transgenic mouse models of breast cancer
- Complex profiling of the cancer transcriptome and epigenome, including at the single-cell level
- High-throughput screening using both compound libraries and CRISPR-Cas9 technology
- Validation of findings in clinical specimens
Although our lab research involves deep interrogation of cell cycle biology in cells and in mice, we aim for each project to culminate in a new therapeutic strategy that can be tested in clinical trials. Indeed, our major findings thus far have all been translated into large-scale clinical trials.
Goel et al, Cancer Cell 2016
In 2016, we published the first report describing the molecular mechanisms by which CDK4/6 inhibitors synergize with receptor tyrosine kinase inhibitors in the treatment of breast cancer. Importantly, this study has led directly to the conduct of two global, randomized trials examining the effect of CDK4/6 inhibitors in HER2-positive breast cancer. Our lab is playing a major role in both of these trials.
Cover image: The battle between targeted therapies and cancer is symbolized by a game of chess, with the king portraying a drug-resistant HER2-positive breast cancer. Acting alone, anti-HER2 therapy (the knight) does not threaten the resistant tumor. However, a CDK4/6 inhibitor (the queen) attacks it directly by inhibiting the phosphorylation of RB. In addition, CDK4/6 inhibition also re-establishes the efficacy of anti-HER2 therapy. It is only when the two agents act in concert that both RB and S6RP phosphorylation are suppressed, maximally inhibiting cell proliferation (holding the king in checkmate).
Goel, DeCristo et al, Nature 2017
In 2017, we published the first report showing that CDK4/6 inhibitors can enhance anti-tumour immune responses. This was an unanticipated finding, and has opened up a new field of research exploring interactions between the cell cycle and cancer immunology. In addition, this work has triggered the development of numerous clinical trials exploring combinations of CDK4/6 inhibitors and immunotherapy.
Importantly, this phenomenon is driven by enhancement of antigen presentation by tumour cells as well as direct effects on immune cells.
Goel et al, Trends in Cell Biology 2018
This review article, highlighted on the cover of Trends in Cell Biology, describes our thinking on the CDK4/6 pathway in cancer.
Pharmacologic inhibitors or cyclin-dependent kinases 4 and 6 (CDK4/6) were developed as inhibitors of cancer cell proliferation. However, CDK4/6 inhibitors can also induce a state resembling cellular senescence, associated with fundamental alterations in the metabolism, immunogenicity, and kinase dependencies of cancer cells. In this image, the smaller flower symbolizes an untreated cancer cell and the larger flower embodies the dramatic biologic changes that take place in response to CDK4/6 inhibition. Treatment reveals unforeseen layers of complexity and at times, exposes new vulnerabilities which might be used to improve therapeutic efficacy.
Watt, Cejas, DeCristo et al, Nature Cancer 2021
In 2021, we published the first report demonstrating that cell cycle inhibitor-induced “senescence” is associated with profound remodelling of cancer cells’ epigenetic landscape. In particular we identified activation of a number of genomic enhancers in treated tumours, and showed that transcriptional activity at these enhancers governs many of the phenotypic effects of these drugs (e.g., luminal differentiation, apoptotic evasion, immunogenicity). This study provided new insights into CDK4/6 pathway biology and will inform the future development of CDK4/6 inhibitors, including the design of novel therapeutic combinations. More broadly, these data highlight the fundamental importance of epigenetic remodelling in therapy-induced senescence.
Uncovering mechanisms of acquired resistance to CDK4/6 inhibition in breast cancer
The majority of patients with metastatic breast cancer will receive a CDK4/6 inhibitor as part of their treatment. Although these drugs are highly effective in most cases, tumours almost invariably acquire resistance to CDK4/6 inhibitors over time. DNA sequencing studies have failed to uncover mutational causes for this resistance in the majority of cases. Indeed for most of our patients, we have no understanding of why their tumour has developed CDK4/6 inhibitor resistance and thus have no good strategies to overcome it. Using unique mouse and cell line models, we are exploring novel, non-mutational mechanisms of CDK4/6 inhibitor resistance.
Impact of CDK4/6 inhibitors on the tumour immune environment
Although several preclinical studies have now demonstrated that CDK4/6 inhibitors enhance anti-tumour immune responses, the precise mechanisms by which this occurs are still poorly understood. In collaboration with colleagues with expertise in immunology and bioinformatics, we are analyzing how CDK4/6 inhibitors alter intratumoural immune cell number and function in unprecedented depth. We believe this research will help determine the ideal immunotherapy partners for CDK4/6 inhibitors.
Characterising CDK4/6 inhibitor-induced “senescence”
CDK4/6 inhibitors activate the RB tumour suppressor, and in doing so induce a cellular phenotype that resembles cellular senescence. In non-cancerous cells, cellular senescence is associated with dramatic alterations in cancer cell metabolism, epigenetic profile, and kinase signalling. However, it is not clear whether these features of classical senescence are recapitulated in tumour cells treated with CDK4/6 inhibitors. Using a variety of in vitro and in vivo approaches, we are exploring the nature of CDK4/6 inhibitor-induced “senescence” searching for changes in cancer cell biology that expose new therapeutic vulnerabilities.
Understanding the role of the RB protein in cancer
CDK4/6 inhibitors promote hypophosphorylation of RB, enforcing its binding to E2F factors and thus blocking the cell cycle. We are actively studying whether RB hypophosphorylation has other transcriptional consequences in cancer cells which might explain the biological effects of CDK4/6 inhibition. In addition, we are studying how loss of RB, a common genomic event in cancer, impacts tumour biology and response to treatment more broadly.
Watt AC, Cejas P, DeCristo MJ, Metzger-Filho O, Lam EYN, Qiu X, BrinJones H, Kesten N, Coulson R, Font-Tello A, Lim K, Vadhi R, Daniels VW, Montero J, Taing L, Meyer CA, Gilan O, Bell CC, Korthauer KD, Giambartolomei C, Pasaniuc B, Seo JH, Freedman ML, Ma C, Ellise M, Krop I, Winer E, Letai A, Brown M, Dawson MA, Long HW, Zhao JJ, Goel S*. Chromatin remodelling underlies key biological effects of CDK4/6 inhibitors. Nature Cancer 2021; 2:34-48.
Heckler M, Ali L, Clancy-Thompson E, Qiang L, Ventre K, Lenehan P, Roehle K, Luoma A, Boelaars K, Peters V, McCreary J, Boschert T, Maul K, Wang E, Sup S, Marangoni F, Mempel T, Long HW, Wucherpfennig KW, Dougan M, Gray N, Yuan GC, Goel S, Tolaney S, Dougan SK. Inhibition of CDK4/6 promotes CD8 T cell memory formation. Cancer Discovery May 2021.
Goel S*, DeCristo M, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, Hoog J, Ellis M, Ma C, Ramm S, Krop IE, Winer EP, Roberts TM, Kim HJ, McAllister SS*, Zhao JJ*. CDK4/6 inhibition triggers anti-tumor immunity. Nature, 2017 Aug; 548(7668): 471-475.
Goel S*, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, Ramm S, Palmer AC, Yuzugullu H, Varadan V, Tuck D, Harris LN Wong K-K, Liu XS, Sicinski P, Winer EP, Krop IE, Zhao JJ*. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell, 2016 March; 29(3):255-69.
Goel S*, DeCristo M, McAllister SS, Zhao JJ*. CDK4/6 inhibition in cancer: beyond cell cycle arrest. Trends in Cell Biology. Published online July 2018. (*co-corresponding author). [PMID: 30061045].
Pernas S, Tolaney SM, Winer, EP, Goel S*. CDK4/6 inhibition in breast cancer: current practice and future directions. Therapeutic Advances in Medical Oncology. Published online July 2018. (*corresponding author). [PMID: 3038670].
Kodack DP, Askoxylakis V, Ferraro GB, Sheng Q, Badeux M, Goel S, Qi XL, Shankaraiah R, Cao A, Ramjiawan R, Bezwada D, Patel B, Song Y, Costa C, Naxerova K, Wong C, Kloepper J, Das R, Tam A, Tanboon J, Duda DG, Miller R, Siegel MB, Anders CK, Sanders M, Estrada MV, Schlegel R, Arteaga CL, Brachtel E, Huang A, Fukumura D, Engelman JA, Jain RK. The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation. Science Translational Medicine, 2017 May; 9(391).
Hydbring P, Wang Y, Fassl A, Li X, Matia V, Otto T, Choi YJ, Sweeney KE, Suski JM, Yin H, Bogorad RL, Goel S, Yuzugullu H, Kauffman KJ, Yang J, Jin C, Li Y, Floris D, Swanson R, Ng K, Sicinska E, Anders L, Zhao JJ, Polyak K, Anderson DG, Li C, Sicinski P. Cell-cycle-targeting MicroRNAs as therapeutic tools against refractory cancers. Cancer Cell, 2017 April; 31(4): 576-590.
Ni J, Ramkissoon SH, Xie S, Goel S, Stover DG, Guo H, Luu V, Marco E, Ramkissoon LA, Kang YJ, Hayashi M, Nguyen QD, Ligon AH, Du R, Claus EB, Alexander BM, Yuan GC, Wang ZC, Iglehart JD, Krop IE, Roberts TM, Winer EP, Lin NU, Ligon KL, Zhao JJ. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nature Medicine, 2016 July; 22(7): 723-26.