Photo of Dr Shankar Varadarajan

Dr Shankar Varadarajan BPharm, ME, PhD

Lecturer Molecular & Clinical Cancer Medicine


BCL-2 family proteins in the regulation of apoptosis

Most cancer chemotherapeutic agents kill tumour cells by activating the intrinsic pathway of apoptosis, which requires the release of cytochrome c from mitochondria. Cancer cells often evade these events by overexpressing one or more anti-apoptotic BCL-2 family of proteins, such as BCL-2, BCL-XL and MCL-1, which function by sequestering and inhibiting their pro-apoptotic counterparts, such as BAX, BAK and BH3-only proteins, such as BIM, BID and NOXA. Disrupting these interactions using small molecule inhibitors (also known as BH3 mimetics) releases the bound pro-apoptotic BCL-2 family members to induce apoptosis. BH3 mimetics, such as Navitoclax (ABT-263) and Venetoclax (ABT-199) have been successfully used in treating several lymphoid malignancies, including chemorefractory chronic lymphocytic leukaemia (CLL). Recently, we reported the potential use of a BCL-XL specific inhibitor in treating TKI-resistant chronic myeloid leukaemia (CML). Similarly, MCL-1-specific inhibitors are currently being developed for use in malignancies, such as multiple myeloma (MM).
Whilst haematological malignancies tend to depend on either BCL-2, BCL-XL or MCL-1, most solid tumours seem to depend on more than one of these members for survival. Given that all these proteins share a common mechanism of action in sequestering BH3-only proteins and antagonising apoptosis, it is intriguing to observe such preferential dependency of different cancers for distinct anti-apoptotic BCL-2 family members. Moreover, these seemingly redundant proteins acquire new, major functions in these malignancies, when cells develop resistance during chemotherapy. Our lab is interested in studying these mechanisms, in an attempt to enhance the therapeutic benefits of BH3 mimetics in overcoming chemoresistance in several cancers.

Endoplasmic Reticulum and mitochondrial membrane dynamics in apoptosis

Changes in mitochondrial membrane dynamics have frequently been associated with the loss of mitochondrial membrane potential, mitochondrial outer membrane permeabilisation (MOMP) and activation of the intrinsic pathway of apoptosis. Indeed, several BH3 mimetics, including ABT-737, and numerous putative MCL-1 inhibitors induce severe perturbations of mitochondrial structure. We recently reported that an MCL-1 inhibitor, A-1210477, induced
extensive mitochondrial fragmentation and this occurred in a DRP-1 dependent manner. DRP-1 is a mitochondrial fission GTPase that not only facilitates mitochondrial fission but is also required for MOMP, thus coupling mitochondrial membrane dynamics and apoptosis. Most recent studies suggest a possible ‘wrapping’ of the Endoplasmic reticulum (ER) around the mitochondria to recruit DRP-1 and Dynamin-2 to facilitate mitochondrial fission and MOMP. Whether BCL-2 family members play critical roles in these events and if so, what are the underlying molecular mechanisms are questions for future research.

Metabolism and apoptosis

Caloric restriction has been reported to modulate MCL-1 expression and alter sensitivity to BH3 mimetic mediated apoptosis in lymphomas. Similarly, targeting metabolic pathways, such as glutaminolysis, has demonstrated promise as combination treatments with BH3 mimetics. This is an interesting avenue to pursue, as metabolic insults have also been implicated in decreasing tumour growth of several malignancies, including KRAS-driven pancreatic ductal adenocarcinoma
(PDAC). In our lab, we are interested in understanding links between such metabolic insults and the mitochondrial apoptotic pathway, in order to explore the
possibility of modulating cellular metabolism to enhance sensitivity to BH3 mimetics.

Research Grants

Novel therapeutic approaches for personalised therapy of Head and Neck cancer


April 2017 - April 2020

Functional characterisation of distinct complexes of MCL-1, an anti-apoptotic BCL-2 family member, in regulating apoptosis in cancer cells


September 2015 - September 2018