s41435-018-0048-6

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Genes & Immunity (2019) 20:529–538
https://doi.org/10.1038/s41435-018-0048-6
REVIEW ARTICLE
Cell death in cancer in the era of precision medicine
Giuseppe Raschellà1 ● Gerry Melino 2,3
● Alessandra Gambacurta2
Received: 3 September 2018 / Revised: 26 September 2018 / Accepted: 1 October 2018 / Published online: 19 October 2018
© Springer Nature Limited 2018
Abstract
Tumors constitute a large class of diseases that affect different organs and cell lineages. The molecular characterization of
cancers of a given type has revealed an extraordinary heterogeneity in terms of genetic alterations and DNA mutations;
heterogeneity that is further highlighted by single-cell DNA sequencing of individual patients. To address these issues, drugs
that specifically target genes or altered pathways in cancer cells are continuously developed. Indeed, the genetic fingerprint
of individual tumors can direct the modern therape.utic approaches to selectively hit the tumor cells while sparing the healthy
ones. In this context, the concept of precision medicine finds a vast field of application. In this review, we will briefly list
some classes of target drugs (Bcl-2 family modulators, Tyrosine Kinase modulators, PARP inhibitors, and growth factors
inhibitors) and discuss the application of immunotherapy in tumors (T cell-mediated immunotherapy and CAR-T cells) that
in recent years has drastically changed the prognostic outlook of aggressive cancers. We will also consider how apoptosis
could represent a primary end point in modern cancer therapy and how “classic” chemotherapeutic drugs that induce
apoptosis are still utilized in therapeutic schedules that involve the use of target drugs or immunotherapy to optimize the
antitumor response.
Cancer therapy in the era of precision
medicine
The heterogeneity of cancer within tumor types and inside
individual tumors is a central issue in oncology [1–3]. Fig. 1
depicts the principle of precision medicine, and how stra-
tification of patients with distinct biochemical character-
istics and survival could be achieved. Indeed, we are now
aware that tumors of the same type cannot effectively be
treated by a single or a limited number of drugs, and the
concept of personalized therapy has become the watchword
in modern oncology [4, 5]. Analysis of genomic DNA
highlighted genetic alterations that vary greatly among
patients bearing tumors with similar histo-pathological
features, although some mutations are more frequent in
specific types of cancer [6, 7]. The hurdle of tumor het-
erogeneity is further highlighted by intratumor hetero-
geneity. With single-cell sequencing techniques, it has been
possible to define cell populations within the tumor of a
single individual that possess a distinctive spectrum of
mutations and that can evolve into cellular subpopulations
with different growth and invasive potential [8]. This latter
point is strictly connected with the urgent need of devel-
oping therapeutic approaches focused on pathology-specific
targets. Classical chemotherapy and radiotherapy, that
indistinctly hit normal and tumor cells, have detrimental and
often life-threatening side-effects [9, 10]. The death of
tumor cells is the final outcome that all anticancer therapies
are aimed at. Nevertheless, killing only cancer cells while
sparing the patient’s normal ones should be the final goal in
oncology in the era of precision medicine [11, 12]. A still
unknown number of genes is altered in tumors by mutations
[13, 14], deletions [15, 16], and epigenetic events [17, 18]
with consequent disorganization of the pathways in which
these genes operate. The development of new antineoplastic
drugs has focused on genes that are more frequently altered
in tumors. Here, we give a brief overview of some types of
biological molecules that have been utilized to develop
targeted therapies.
* Giuseppe Raschellà
giuseppe.raschella@enea.it
1 ENEA Research Center Casaccia, Laboratory of Biosafety and
Risk Assessment, Via Anguillarese, 301, 00123 Rome, Italy
2 Department of Experimental Medicine TOR, University of Rome
“Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
3 Medical Research Council, Toxicology Unit, Hodgkin Building,
University of Cambridge, Leicester LE1 9HN, UK
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http://orcid.org/0000-0001-9428-5972
http://orcid.org/0000-0001-9428-5972
http://orcid.org/0000-0001-9428-5972
http://orcid.org/0000-0001-9428-5972
http://orcid.org/0000-0001-9428-5972
mailto:giuseppe.raschella@enea.it
Bcl-2-family modulators
Apoptosis is frequently deranged in cancer cells so that
survival advantage and resistance to therapy are acquired
[19, 20]. The apoptotic process is complex and involves
many factors located on the cell membrane, in the mito-
chondria, and in the cytoplasm. Mitochondrial apoptosis is
controlled by the Bcl-2 family that includes proapoptotic
and antiapoptotic factors [21–23]. In this family, inhibitors
of apoptosis are BCL-2, BCL-XL, BCL-W, BFL-1, and
MCL-1 while the inducers have been divided into BH3-only
factors (e.g. BIM, BID, BAD, NOXA, and PUMA) and
effectors such as BAK and BAX (reviewed in Ref. [24]).
Several posttranscriptional modifications of the BH3-only
factors trigger their oligomerization, which causes a per-
meabilization of the mitochondrial membrane, the con-
sequent release of cytochrome C into the cytoplasm, the
activation of Caspase 9, and the execution of the final part
of the apoptotic process [22, 24, 25]. In general, the func-
tion of the antiapoptotic proteins of the Bcl-2 family is to
bind the proapoptotic factors of the BH3-only type [26],
preventing their function. In autoimmune diseases [27, 28]
as well in tumors [29–31], antiapoptotic Bcl-2 proteins are
often overexpressed thus preventing the normal apoptotic
DRUG
Alterna�ve
Treatment
Precision Medicine
hypothesis
Screen Select
SER, GLY, GLN, TAp73 biomarkers
of the One Carbon Metabolism
Bcl2 family screen for Cell Death
Checkpoints for Immunotherapy
e.g.
To predict response to therapy?
To stra�fy selected pa�ents?
To reduce wanton toxicity?
To improve overall survival?
aim
Fig. 1 General principles of
Precision Medicine in Cancer.
The ex vivo analysis of
expression and sensitivity to
distinct therapies, such as e.g.,
one carbon metabolism, cell
death, or immunotherapy, allows
the selection and stratification of
patients with distinct
biochemical patterns that are
sensitive to individually tailored
therapies. This improves
efficacy and survival, while
reducing wanton toxicity
BCL-2 BCL-XL BCL-W 
BFL-1 and MCL-1
Cyt C
BAX
B vator
+ + +A B C
BAK
BH3 mime cs
Bcl-2 inhibitors
MITOCHONDRION
APOPTOSIS
Cyt C
Cyt C MITOCHONDRION
BIM, BID, BAD, 
NOXA and PUMA 
Bcl-2 family
An -apopto c factors
Pro-apopt c factors
Drugs
Fig. 2 Modulators of the Bcl-2 family: mechanisms of action. a BH3
mimetics act by displacement of antiapoptotic proteins (BCL-2, BCL-
XL, BCL-W) from binding proapoptotic factors (BIM, BID, BAD,
NOXA, and PUMA). b Bcl-2 inhibitors cause the inhibition of the
activity of Bcl-2 antiapoptotic proteins. At present, there are not BH3
mimetics nor Bcl-2 inhibitors with significant activity on BFL-1 and
MCL-1. c BAX activator acts by binding to a hydrophobic task of
BAX protein and triggering its activity in a BAK-independent manner.
The actions in a, b, and c cause mitochondrial membrane depolar-
ization, release of cytochrome C in the cytoplasm and apoptosis in
cancer cells. Symbols legends of the members of the Bcl-2 family and
of the drugs that modulate their activity are on the right of the figure
530 G. Raschellà et al.
process and favoring the onset of resistance to anti-
neoplastic therapies. For this reason, drugs that mimic BH3-
only factors binding to the antiapoptotic proteinsof the Bcl-
2 family have been devised (BH3-mimetic small molecules
such as ABT-199 and ABT-263) [32, 33]. These drugs
displace BH3-only factors from binding to the antiapoptotic
proteins of the Bcl-2 family allowing the onset of mito-
chondrial apoptosis. Furthermore, small molecules have
been generated that specifically inhibit the activity of the
antiapoptotic factor Bcl-XL [34] while others of plant
derivation, act as general inhibitors of the antiapoptotic Bcl-
2 proteins (Gossypol) [35]. A different type of approach has
been to design small molecules that act as direct activators
of the proapoptotic factor BAX [36]. In human lung cancer
cells, a small molecule of this type was able to bind the
hydrophobic binding pocket of BAX [37], thus inducing its
activity without significant normal tissue toxicity [38]. Fig.
2 schematizes the mechanisms of action of drugs acting by
modulating factors of the Bcl-2 family. Very recent updates
on this issue could be expanded reading the reviews by
Montero and Letai [39], Adams and Cory [40], and Reed
[41].
Tyrosine kinase inhibitors
Although cell death is the desired final outcome for cancer
cells, the apoptotic machinery is not always the primary
target in modern cancer therapy. Signaling pathways that
control growth, differentiation, motility, and metabolism are
altered in tumors by mutation or inappropriate expression
[42–44]. Tyrosine kinases (TKs) play a central role in
relying signals along pathways and their activity is often
compromised in tumors [45, 46]. These enzymes are often
accessible on the cell membrane or in the cytoplasm. TK
inhibitors (TKIs) that selectively target abnormal TKs have
stably entered anticancer therapy [47, 48]. The progenitor of
these molecules has been Imanitib-mesilate (Gleevec), a
small molecule that acts as an inhibitor of the chimeric
tyrosine kinase Bcr-Abl [49, 50]. This drug profoundly
changed the therapeutic approach and clinical outcome of
chronic myeloid leukemia (CML) patients, and other Bcr-
Abl inhibitors have entered therapy when Imanitib-mesilate
resistance occurs [51, 52]. Although the specificity of TKIs
is not always complete, this feature has been used to extend
their use to other pathologies where other tyrosine kinases
are inappropriately expressed. This is, for example, the case
of neuroblastoma, a childhood aggressive cancer [53],
where the TKI Dasatinib is able to induce downregulation
of c-Kit and c-Src phosphorylation and tumor shrinkage in
preclinical models [54]. Nowadays, a continuously growing
number of other small molecules that target mutated/
overexpressed tyrosine kinases are entering therapy for
many types of cancer [55–57].
PARP inhibitors
Genomic instability is one of the distinctive features of
tumors [58–61]. Instability is recognized by chromosome
alterations (in structure and number) and subtler but equally
dangerous changes in the structure of DNA such as muta-
tions [62, 63], deletions [64, 65], and rearrangements [66].
The integrity of genomic DNA is continuously challenged
by physical and chemical agents that can directly cause
damage on the DNA or, in presence of deranged repair
activity, may cause the establishment of dangerous muta-
tions [67]. The machinery of DNA repair is complex and
includes many core factors [68, 69] as well as accessory
proteins [70–72] whose loss can generate suboptimal repair
potential. Recently, also RNAs entered the arena of DNA
repair although the mechanism(s) of action of RNA in this
process remain largely unknown [73]. If from a given point,
instability plays a protumor role allowing the development
of cell populations with a better survival ability [74],
enhanced proliferation and invasiveness potential, on the
other end it represents a weakness that can be therapeutically
exploited [75]. Cells react to a genotoxic stress [76] by
activating a number of specific repair pathways that collec-
tively take the name of DNA-damage response (DDR) [77].
A central player for the correct implementation of the DDR
is PARP, which acts as a sensor of the genotoxic damage by
blocking the cell cycle and allowing the coordinated activity
of the DDR factors although PARP activity is also required
for the autophagic process [78]. Some decades ago, analogs
of nicotinamide with PARP inhibitory activity were descri-
bed [79, 80]. Over the years, numerous more specific and
powerful drugs that inhibit PARP activity have been dis-
covered [81, 82] and some of these have entered anticancer
therapy [83]. Indeed, the use of small molecule Olaparib was
approved for gynecological cancers bearing germ line and
somatic mutations of BRCA as well as in castration-resistant
prostate cancers [84, 85]. In addition, Talazoparib showed
therapeutic activity in early-stage breast cancer bearing
mutations of BRCA1 and BRCA2 [86].
Growth factor inhibitors
Growth factors and their ligands have been used as targets
for anticancer therapies. It is well known that tumors use
autocrine and paracrine signals for their growth and meta-
static spreading [87, 88]. Pioneering work by Folkman
clearly established that tumors need to be vascularized to
Cell death in cancer in the era of precision medicine 531
growth [89]. Indeed, a tumor mass remains dormant until a
bed of capillaries infiltrate the tumorous cells promoting
their proliferation [90]. The discovery of a family of growth
factors that regulate angiogenesis was crucial for the
development of antiangiogenic therapies (reviewed in Ref.
[91]). Vascular endothelial growth factors (VEGFs) are a
family of proteins that includes VEGFA, VEGFB, VEGFC,
VEGFD, and the placental growth factor. Specific receptors
endowed with tyrosine kinase activity (VEGFRs), transduce
the VEGF signals into the cells (reviewed in Ref. [91]).
Many small molecules and specific antibodies that are
antagonistic to the VEGF pathways have now routinely
entered therapy and have significantly changed the prog-
nostic outlook of common cancers such as breast cancer,
lung carcinoma, renal cell carcinoma, thyroid, and prostate
cancer (reviewed in Ref. [92]).
Other growth factors that have been used as targets for
anticancer therapies are the insulin-like growth factors (IGF1
and IGF2) and their receptor (IGF1R). Indeed, a direct link
between the level of IGF1 in the blood and the risk to develop
the breast, colon, lung, and prostate cancers has been demon-
strated [93]. Several small molecules and antibodies were
developed to antagonize the activity of the IGF factors and their
receptors (reviewed in Ref. [94]). In a study, the small molecule
NVP-AEW541 was demonstrated to inhibit the activity of
IGF1R. In nude mice, this molecule reduced the growth of
tumors derived from 3T3 cells overexpressing IGF1R [95]. Of
interest, NVP-AEW541 was also able to inhibit the growth and
metastatic spreading of IGF2-expressing neuroblastoma tumors
in immune-deficient mice [96].
Biochemical profiling
Since the time of Otto Warburg, metabolism had been
considered the Achilles’ heel of cancer cells; recent devel-
opments in this field may indeed offer innovative ther-
apeutic venues in cancer therapy. While there is a profound
metabolic flux adaptation during development [97] as well
as in overt tumors [98–102], recent work by Karen Vousden
in different mouse models, shows the efficacy of serine and
glycine dietary restriction [103]. We have recently shown
that a particular p53 family member, p73 [104–106] can
actually predict sensitivity of medulloblastoma cells to
glutamine diet restriction, affecting chemosensitivity and
survival [107]. This action is at least in part regulated by a
selective translation mechanism [108].
Cancer immunotherapy
To conclude this brief overview of the targeted therapies in
use for cancer treatment, it is necessary to mention
immunotherapy that has revolutionized the clinical man-
agement of some aggressive tumors (e.g., metastatic mela-
noma). Tumors as well as other human pathologic
conditions express a variety of immunological and inflam-
matorycytokines that affect the immune system and its
response to cancer cells [109–113]. The purpose of cancer
immunotherapy is to boost a process of anticancer immu-
nity [114–117], that is durable while avoiding unwanted
autoimmune attack and uncontrollable inflammatory
responses that are common in other chronic diseases[118,
119]. For this reason, cancer immunotherapies should have
a very strict control that prevents unrestrained amplification
of the immune response and allows to halt or slow down the
antitumor response in case of damage to non-cancerous
cells and organs. Broadly, cancer immunotherapy can be
divided in two main approaches: (i) stimulation of host T-
cell-mediated immune response against cancer cells that are
recognized as non-self [120, 121] and (ii) engineering
T cells of the patient into chimeric T cells (CAR-T) directed
against specific tumor antigens that can be grown in large
numbers ex vivo and reinjected in the patient’s blood to
boost antitumor attack [122–125]. Some modulators are
expressed by cancer cells to prevent the attack by the
immune defenses of the host [126]. PD-L1, a modulator that
restrains the antitumor attack of T-cells [127–129], is
expressed in a consistent number of cancers, therefore,
several immunotherapies have been devised to prevent
binding of PD-L1 to its receptor PD1. Encouragingly, anti-
PD-L1 or anti-PD-1 monotherapies gave a striking ther-
apeutic response within days from the initial treatment in a
broad range of cancers although in other cases they were
completely ineffective [130]. Immune checkpoint blockade
is a revolutionary new approach to cancer treatment that
would not exist without the fundamental contributions of
Tak Mak, Mark Davis, and James Allison. In 1984, Drs.
Mak and Davis independently cloned the cDNAs encoding
chains of the human and mouse T-cell antigen receptor
(TCRs), respectively, establishing the foundation of modern
T-cell immunology [131, 132]. In 1995, Dr. Mak’s group
was the first to definitively demonstrate that the T cell
surface molecule CTLA4 acts as a checkpoint in that it
negatively regulates T-cell activation [133]. In 1996, Dr.
Allison and collaborators insightfully built on this knowl-
edge to devise a new approach to cancer therapy based on
antibody-mediated blocking of CTLA4-mediated T cell
suppression [134]. Where CTLA4 function is absent or
reduced, a TCR cell-mediated response to a cancer is not
shut down and can continue to attack the malignancy,
eventually helping to control tumor growth and in some
cases eradicate it. This concept has now been extended to
another T cell activation checkpoint (CTLA4/PD-1/PDL-1/
other receptors). The immune blockade approach has been
successfully translated to the clinic, where it has been
532 G. Raschellà et al.
effective in treating several aggressive cancers for which
there was previously no effective treatment.
Adoptive T cell transfer (ACT) is the infusion of T
lymphocytes [135] that mediate an antitumor effect [136,
137]. Beside ACT-therapies based on the expansion and
reinfusion of autologous antitumor T cells [138], a pro-
mising strategy that has been already applied, relies on the
ex vivo engineering of patient-derived T cells to make them
able to recognize specific tumor antigens. In 1989, Dr. Zelig
Eshhar insightfully built on this knowledge to devise a new
method of cancer therapy. He designed a hybrid molecule
composed of an antibody variable region that recognized a
tumor-associated surface marker such as CD19 or CD20
and structurally fused it to part of a TCR [139]. This chi-
meric antigen receptor (CAR-T) then facilitated T cell-
mediated killing of cancer cells expressing the marker.
CAR-T therapy has been approved for the treatment of
several aggressive relapsed or refractory cancers, including
leukemias and lymphomas, and has saved the lives of
thousands of cancer patients to date. T cell-mediated
assaults on solid tumors may soon be possible with this
TCR-based methodology. The chimeric antigen receptor
(CAR) is composed of a single-chain fragment derived from
the variable domains of antibodies (scFv) that acts as
antigen-binding domain fused to intracellular signaling
portions of the T-cell receptor (TCR) and costimulatory
endo-domains such as CD28 or 4-1BB or both [140]. Dif-
ferently from endogenous TCRs, engineered CAR-T cells
recognize antigens in a MHC-independent manner. How-
ever, the latter point limits the development of CAR-T cells
to the recognition of extracellular surface antigens. Never-
theless, the latter point could allow the future use of CAR-T
cells to treat infection autoimmunity [141, 142] and allo-
transplantation [143].
Resistance to CAR-T cell-based therapies can develop by
the loss of the surface antigen against which the CAR-T is
directed to, by development of anti-CAR-T antibodies, or
by the lack of persistence of CAR-T cells after injection in
the patient [144]. It should be stressed that the success of
immune-therapies (not only CAR-T cell-based therapies) is
strictly dependent on in situ immune infiltration. Some
tumors are highly infiltrated by cells of the immune system
(and are likely prone to respond) while others appear as
immune deserts and are frequently resistant [145]. For
instance, the degree of inflammation is in fact a central
parameter for therapeutic success [146, 147]. In addition,
we should keep into account the specificity of the infiltrat-
ing T cells against tumor antigens since other nonspecific
T cells [148] are not useful for treatment [140]. Immu-
notherapy by autologous transfer of T cells and by CAR-T
cells is illustrated in Fig. 3.
Apoptosis as primary target or additive end
point in combined anticancer therapies
How apoptosis intersects these new therapeutic approaches?
Does it only represent a possible end point of the above
described targeted treatments or proapoptotic therapies
[149] can be used in parallel to obtain more complete
response? Indeed, Doxorubicin (a chemotherapeutic drug
and potent apoptosis inducer) has been successfully utilized
prior to Tumor Infiltrating Lymphocytes (TILs) or CAR-T-
cell infusion to promote infiltration of NKG2D+ CD8+
VL
VHscFv
Hinge
endo-domains
TUMOR
Tumor associated
an gen
A
B
Transgenic TCR
CAR-T
ε
δ
α
β
γ
ε
ζ
ζ
ζ
Fig. 3 T-cell-mediated therapy of tumors. a T-cell receptor (TCR) can
be engineered to recognize specific tumor antigens on the surface of
cancer cells. b Chimeric antigen receptor T (CAR-T) can be described
as a simplified version of TCR. CAR-T is made of the extracellular
domain of an antibody and a signaling intracellular moiety (ζ) from
T cells. The newer versions of CAR-T are endowed with costimulatory
endo-domains such as CD28 and 4-1BB in the intracellular part. Cells
bearing antitumor CAR-T can be grown in large numbers ex vivo and
reinjected in patients. VH variable heavy chain, VL variable light
chain, scFv single-chain variable fragment
Cell death in cancer in the era of precision medicine 533
T cells in xenographs of solid tumors in mice [150]. In
addition, etoposide, a Topoisomerase II inhibitor that
induces apoptosis, has been used for lympho-depletion
before infusion of CD19 CAR-T cells in adult B-cell acute
lymphoblastic leukemia patients [151].
In conclusion, apoptosis is still a cellular mechanism that
can be exploited directly in tumor targeted therapy (e.g.,
Bcl-2-family modulators) but also, using proapoptotic che-
motherapeutic drugs as a resource to make an effective
eradication of cancer cells (Fig. 4). The combined use of
target drugs and immunotherapy with proapoptotic drugs
could also allow the use of less toxic but more efficient
therapeutic regimens.
Acknowledgements This work has been supported by the Medical
Research Council, UK; grants from Associazione Italiana per la
Ricerca contro il Cancro (AIRC): AIRC 2017 IG20473 (to G.M.) and
Fondazione Roma malattie Non trasmissibili Cronico-Degenerative
(NCD) Grant (to G.M.).
Compliance with ethical standards
Conflict of interest Theauthors declare that they have no conflict of
interest.
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GF Inhibitors
PARP inhibitors
Immunotherapy
Check points inhibitors
CAR-T cells
Bcl-2 family
modulators
TUMOR KILLING
Molecular 
characteriza�on 
of tumors
SAMPLEPrecision Medicine
in ONCOLOGY
CHEMOTHERAPY
(pro-apopto�c drugs)
Fig. 4 Precision medicine in oncology is based on the molecular
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538 G. Raschellà et al.
	Cell death in cancer in the era of precision medicine
	Abstract
	Cancer therapy in the era of precision medicine
	Bcl-2-family modulators
	Tyrosine kinase inhibitors
	PARP inhibitors
	Growth factor inhibitors
	Biochemical profiling
	Cancer immunotherapy
	Apoptosis as primary target or additive end point in combined anticancer therapies
	Compliance with ethical standards
	ACKNOWLEDGMENTS
	References