Sk. Kayum Alam

Postdoctoral Research Associate , Ph.D.

20162017
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Personal profile

Research interests

1. Combating EGFR tyrosine kinase inhibitor resistance in non-small cell lung cancer

Lung cancer is the deadliest and most frequently diagnosed type of tumor. We recently demonstrated that dopamine and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32), and its truncated splice variant, t-DARPP, promotes non-small cell lung cancer (NSCLC) growth in orthotopic mouse models. Immunostaining of 62 human lung adenocarcinoma tissues showed that t-DARPP expression is elevated with increasing tumor (T) staging score, a metric of tumor progression and growth. Bioinformatics analysis revealed upregulation of t-DARPP correlates with advanced T stage and poor overall survival of NSCLC patients. We showed DARPP-32 and inhibitory kappa B kinase-alpha physically interact to drive NSCLC cell migration through activation of non-canonical NF-kappaB2 signaling.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the recommended first-line therapy for NSCLC patients harboring EGFR mutations. Despite initial responsiveness, EGFR-mutant NSCLC inevitably progresses in most patients within one year. Acquired resistance to EGFR TKIs is a major problem because the mechanisms of resistance are poorly understood. Our in vivo studies show upregulation of DARPP-32 isoforms promotes EGFR-mutant NSCLC growth and drives resistance to EGFR inhibitors. We propose a novel mechanism of acquired resistance to EGFR TKIs in NSCLC, in which DARPP-32 mediates a switch from EGFR TKI-sensitive EGFR homodimers to TKI-resistant EGFR:ERBB3 heterodimers. To date, no proteins have been identified that are capable of mediating such a “dimerization switch” in EGFR-mutant NSCLC. Our data supports a model in which DARPP-32 physically recruits ERBB3 to EGFR to mediate the EGFR:EGFR to EGFR:ERBB3 shift to overcome EGFR TKI-induced apoptosis by potentiating AKT and ERK signaling in NSCLC. Investigation of the role of DARPP-32 isoforms in EGFR-mutant NSCLC remains unexplored, and our work has the potential to lay the groundwork for the development of therapies designed to circumvent TKI refractory NSCLC progression to improve the quality of life and clinical outcome for patients.

2. ASCL1-regulated DARPP-32 and t-DARPP stimulate small cell lung cancer growth and neuroendocrine tumor cell survival

Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, and new molecular insights are necessary for prognostic and therapeutic advances. Here we demonstrate in orthotopic mouse models that dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32) and its N-terminally truncated splice variant t-DARPP promote SCLC growth through increased proliferation, Akt/Erk-mediated survival and anti-apoptotic signaling. DARPP-32 and t-DARPP proteins are overexpressed in SCLC patient-derived tumor tissue, but virtually undetectable in physiologically normal lung. RNA sequencing analysis reveals a subset of SCLC patients with high tumoral t-DARPP expression and upregulated Notch signaling genes, including achaete-scute homologue 1 (ASCL1). We show that DARPP-32 isoforms are transcriptionally activated by ASCL1 in human SCLC cells. Taken together, we demonstrate new regulatory mechanisms of SCLC oncogenesis that suggest DARPP-32 isoforms may represent a negative prognostic indicator for SCLC and serve as a potential target for the development of new therapies.

 

Education/Academic qualification

PhD, IICB

Jul 28 2009Feb 10 2016

Research interests

  • Drug Resistance
  • Lung Cancer
  • EGFR Tyrosine Kinase Inhibitors
  • Small cell lung cancer
  • Dopamine Signaling

Fingerprint The Fingerprint is created by mining the titles and abstracts of the person's research outputs and projects/funding awards to create an index of weighted terms from discipline-specific thesauri.

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Research Output 2016 2017

7 Citations (Scopus)

p53 gain-of-function mutations increase Cdc7-dependent replication initiation

Datta, A., Ghatak, D., Das, S., Banerjee, T., Paul, A., Butti, R., Gorain, M., Ghuwalewala, S., Roychowdhury, A., Alam, S. K., Das, P., Chatterjee, R., Dasgupta, M., Panda, C. K., Kundu, G. C. & Roychoudhury, S., Nov 2017, In : EMBO Reports. 18, 11, p. 2030-2050 21 p.

Research output: Contribution to journalArticle

Open Access
Mutation
Cells
Neoplasms
Peptide Initiation Factors
DNA Replication
38 Citations (Scopus)

DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53

Alam, S. K., Yadav, V. K., Bajaj, S., Datta, A., Dutta, S. K., Bhattacharyya, M., Bhattacharya, S., Debnath, S., Roy, S., Boardman, L. A., Smyrk, T. C., Molina, J. R., Chakrabarti, S., Chowdhury, S., Mukhopadhyay, D. & Roychoudhury, S., Apr 1 2016, In : Cell Death and Differentiation. 23, 4, p. 707-722 16 p.

Research output: Contribution to journalArticle

Open Access
Ephrin-B2
Epithelial-Mesenchymal Transition
DNA Damage
Colorectal Neoplasms
p53 Genes
11 Citations (Scopus)

E2 ubiquitin-conjugating enzyme, UBE2C gene, is reciprocally regulated by wild-type and gain-of-function mutant p53

Bajaj, S., Alam, S. K., Roy, K. S., Datta, A., Nath, S. & Roychoudhury, S., Jul 1 2016, In : Journal of Biological Chemistry. 291, 27, p. 14231-14247 17 p.

Research output: Contribution to journalArticle

Open Access
Ubiquitin-Conjugating Enzymes
M Phase Cell Cycle Checkpoints
Anaphase
Genes
Ubiquitin
19 Citations (Scopus)

MicroRNA profiling of cisplatin-resistant oral squamous cell carcinoma cell lines enriched with cancer-stem-cell-like and epithelial-mesenchymal transition-type features

Ghosh, R. D., Ghuwalewala, S., Das, P., Mandloi, S., Alam, S. K., Chakraborty, J., Sarkar, S., Chakrabarti, S., Panda, C. K. & Roychoudhury, S., Apr 5 2016, In : Scientific reports. 6, 23932.

Research output: Contribution to journalArticle

Open Access
Epithelial-Mesenchymal Transition
Neoplastic Stem Cells
MicroRNAs
Cisplatin
Squamous Cell Carcinoma
7 Citations (Scopus)

Transcriptome profiling identifies genes and pathways deregulated upon floxuridine treatment in colorectal cancer cells harboring GOF mutant p53

Datta, A., Dey, S., Das, P., Alam, S. K. & Roychoudhury, S., Jun 1 2016, In : Genomics Data. 8, p. 47-51 5 p.

Research output: Contribution to journalArticle

Open Access
Floxuridine
Gene Expression Profiling
Colorectal Neoplasms
Genes
Cells