Abstract
Small cell lung cancer (SCLC) remains a deadly form of cancer, with a 5-year survival rate of less than 10 percent, necessitating novel therapies. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is emerging as a therapeutic target and is co-expressed with BCL2 in multiple tumor types due to microRNA coregulation. We hypothesize that ROR1-targeted therapy is effective in small cell lung cancer and synergizes with therapeutic BCL2 inhibition. Tissue microarrays (TMAs) and formalin-fixed paraffin-embedded (FFPE) SCLC patient samples were utilized to determine the prevalence of ROR1 and BCL2 expression in SCLC. Eight SCLC-derived cell lines were used to determine the antitumor activity of a small molecule ROR1 inhibitor (KAN0441571C) alone and in combination with the BCL2 inhibitor venetoclax. The Chou-Talalay method was utilized to determine synergy with the drug combination. ROR1 and BCL2 protein expression was identified in 93% (52/56) and 86% (48/56) of SCLC patient samples, respectively. Similarly, ROR1 and BCL2 were shown by qRT-PCR to have elevated expression in 79% (22/28) and 100% (28/28) of SCLC patient samples, respectively. KAN0441571C displayed efficacy in 8 SCLC cell lines, with an IC50 of 500 nM or less. Synergy as defined by a combination index of <1 via the Chou-Talalay method between KAN0441571C and venetoclax was demonstrated in 8 SCLC cell lines. We have shown that ROR1 inhibition is synergistic with BCL2 inhibition in SCLC models and shows promise as a novel therapeutic target in SCLC.
Highlights
Small cell lung cancer (SCLC) has a 5-year survival rate of only 6 percent, with no approved targeted therapies, underscoring the need for novel therapeutics[1]
receptor 1 (ROR1) expression was identified in 93% (52/56) of SCLC tumors, while BCL2 expression was identified in 86% (48/56) of SCLC tumors, and 83% (45/56) of SCLC tumors showed expression of both ROR1 and BCL2 in the same tumor cells
We determined that there is a negative correlation between the expression of the miRNAs and the expression level of BCL2 and ROR1, suggesting that the expression of these miRNAs may act as a negative regulator of ROR1 and BCL2 expression in SCLC as previously described in CLL6,25
Summary
Small cell lung cancer (SCLC) has a 5-year survival rate of only 6 percent, with no approved targeted therapies, underscoring the need for novel therapeutics[1]. Receptor tyrosine kinase-like orphan receptor 1 (ROR1). Is a receptor tyrosine kinase-like protein that has been implicated to play a role in many different types of cancer[3,4,5,6,7,8]. ROR1 has oncofetal expression, as it is an embryonic protein that is not normally expressed in differentiated cells, but can be re-expressed in cancer cells[9]. ROR1 inhibition has been shown to lead to cell death in pancreatic, leukemia, and lung cancer cells, suggesting that it is a viable therapeutic target[4,7,10,11,12,13]
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