Shom Goel

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.

Key Achievements

​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. 

For all enquiries related to The Goel Laboratory contact Zoë Gordon