Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics

Abstract

To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.

Keywords: Mevalonate and Purine biosynthesis; breast cancer hard-to-treat cancers; cancer fitness genes; oncology drugs; repurposing.

Figure 1

Oncology drug targets and/or effectors as good or poor cellular fitness genes. (A) Strategy to examine the fitness- dependency of cancer types for which oncology drugs targeting these targets are either approved or not approved. (B) Distribution of 43 cancer targets and/or effectors of FDA-approved drugs, a subset of 14 targets shared with 628 priority therapeutic targets and common targets between these two groups across cancer types, for which drugs targeting these cellular targets are not approved. (C) Distribution of significant fitness dependency of 47 molecules across 19 cancer types, for which drugs targeting these molecules are either approved (dark green boxes) or not approved (light green boxes). Here, n—collective number of target fitness values among cancer cell lines in a given cancer type; one dot per target per cell line.

Figure 2

Revelation of cellular molecules with differential effects on cellular fitness. (A) Overall distribution of the 88 cancer targets with no loss of cellular fitness upon depletion across the 19 types of cancer cell lines. (B) Distribution of the positive fitness effect of depleting the 47 targets across cancer types, for which drugs utilizing these molecules are either approved or not approved. Here, n—collective number of target fitness values among cancer cell lines in a given cancer type; one dot per target per cell line. (C) Representative examples of the three fitness genes important in the action of bevacizumab in the three referred cancer types. (D) Selected examples of the above representative targets in cancer-types for which drugs targeting these molecules are approved using data from Drug bank and corresponding Fitness score for were derived from the Cancer Dependency Map.

Figure 3

Distribution of fitness genes in a sub-set of cancer types. (A) Distribution of the 43 cancer cell fitness genes with a significant loss of cellular fitness upon depletion across the 19 cancer types. (B) Distribution of the loss of cellular fitness upon depletion of targets of either approved (dark green) or not approved (light green) oncology drugs in breast cancer, pancreatic cancer, or glioblastoma.

Figure 4

Expression of GGPS1, FDPS, HMGCS1 and GART in breast cancer. (A) Amplification and expression of indicated molecules in breast tumors in The Cancer Genome Atlas (TCGA) (left) and Metaberic data (right) [49] using Copy Number Variation (CNV) and gene alteration rate data from cBioPortal.org [29,30]. (B) Expression of GGPS1, FDPS, GART and 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1 (HMGCS1) mRNAs in breast cancer sub-types, in breast tumors and adjacent matched normal tissues using the data from cBioPortal (left panel) [29,30] and from Xena Browser (right panel) [31]. (C—E) Expression of indicated four mRNAs in TNBC and matched normal tissues from Xena Browser (right panel) [31], in TNBC samples [50], in TNBC and non-TNBC breast tumors, and breast cancer cell lines [51]; Right panel: Gene expression representation using heatmap in breast cancer cell lines—AU565, BT20, BT474, BT483, BT549, CAL120, CAL148, CAL51, CAL851, CAMA1, DU4475, EFM192A, EFM19, HCC1143, HCC1187, HCC1395, HCC1419, HCC1428, HCC1500, HCC1569, HCC1599, HCC1806, HCC1937, HCC1954, HCC202, HCC2157, HCC2218, HCC38, HCC70, HDQP1, HS274T, HS281T, HS343T, HS578T, HS606T, HS739T, HS742T, JIMT1, KPL1, MCF7, MDAMB134VI, MDAMB157, MDAMB175VII, MDAMB231, MDAMB361, MDAMB415, MDAMB436, MDAMB453, MDAMB468, SKBR3, T47D, UACC812, UACC893, YMB1, ZR751, ZR7530, EVSAT and HMC18 cells using data from cBioPortal.org [29,30].

Figure 5

Coexpression and significance of GGPS1, FDPS, GART and HMGCS1 in breast cancer. (A) Proteogenomics expression status of the four indicated molecules in breast tumors. Yellow: CNV, Green:a RNAseq, and Orange: Protein [48]. (B) SurvExpress [32] survival analysis of GGPS1, FDPS, and GART and that of GGPS1, FDPS, GART, and HMGCS1 in patients with breast tumors.

Figure 6

Fitness dependency of the four enzymes of the mevalonate/cholesterol pathway in cancer-types. (A). Status of cellular fitness of cancer types upon knocking out GGPS1, FDPS, HMGCS1, or GART in cancer types for which drugs utilizing these molecules are approved (dark green dots) or not approved (light green) or are non-oncology drugs (orange). (B) Relationship between the four cellular targets or effectors and fitness dependency of cancer types, for which indicated drugs targeting these molecules are not approved.

Figure 7

Relationship between the cellular targets and/or effectors of oncology drugs and cancer-types. Overall summary of the relationship noticed in the present study between the cancer types and cellular targets or effectors with significant fitness-dependency for which indicated drugs targeting these molecules are not approved (A) or approved (B).