Drug Resistance
Despite the major advances we have made in treating cancer,
many tumors are not completely eliminated by the therapies that
we currently use and, over time, become resistant to a given
therapy and continue to progress.
Drug resistance is of two types: acquired resistance, which
develops during the course of treatment in response to therapy,
and innate resistance, which is inherent and present even before
treatment with a given therapy begins. It is one of the greatest
challenges that we face today in cancer treatment.
Diversity among the cancer cells in a single tumor is a key driver
of acquired resistance to treatment with both cytotoxic and
molecularly based therapeutics. For example, many cytotoxic
drugs are designed to target only rapidly dividing cells, and so
cells within a cancer that are not rapidly dividing escape these
treatments. In addition, dividing cancer cells accumulate new
genetic changes at a high rate. In cancers being treated with
molecularly targeted therapies, if one cell gains a new mutation
that alters the drug target itself, the drug may be ineffective
against that cell, which will then continue dividing.
Redundancies among the signaling networks that fuel cancer
cell proliferation can also permit cells to become resistant to
molecularly targeted therapies. In this case, the initial therapeutic
can block a signaling pathway in the network, but the cell uses a
“detour” around the blockade and continues proliferating.
Some patients, despite having the molecular defect that matches
a given molecularly targeted drug, do not respond to the therapy
because of innate resistance. This may be because of genetic
mutations present in the cell itself, or it could be because of
a variation in the patient’s genome that alters drug activity or
metabolism, or a combination of the two.
To develop therapies that will overcome drug resistance, we
need to continue making inroads in understanding the ways by
which cancers become drug resistant, as well as the factors
within the tumor and the patient that drive resistance. This will
only be possible with continued investment in the research to
do so.
pomalidomide benefits patients with multiple myeloma
that has progressed after treatment with earlier generation
immunomodulatory drugs (142).
Lessons Learned From CML
Imatinib (Gleevec) was the first molecularly targeted chemical
approved by the FDA for the treatment of a cancer, CML. Its
development was the result of a series of groundbreaking
scientific discoveries (see Figure 14, p. 51). Imatinib blocks
the activity of an aberrant protein called BCR-ABL, which
fuels most cases of CML. Five-year survival rates for CML
increased from just 31 percent to around 90 percent following
the 2001 FDA approval of imatinib ( 1, 143). Unfortunately, a
small fraction of patients never respond to imatinib, while other
patients initially respond, but eventually their leukemia returns,
or relapses, having acquired resistance to the drug (see sidebar
on Drug Resistance).
Researchers have determined that imatinib-resistant leukemias
harbor unique forms of BCR-ABL that cannot be blocked by
the drug. Two second-generation drugs, dasatinib (Sprycel)
and nilotinib (Tasigna), that are able to block most of these
distinctive BCR-ABL proteins, were developed and approved
by the FDA in 2006 and 2007, respectively. However, all three
drugs fail to block one particular form of BCR-ABL, called
T315I, which remains a significant challenge.
Three FDA decisions in the last four months of 2012 should
help address this serious clinical issue and has increased
the number of treatment options for patients with imatinib-resistant CML. The first was the September 2012 FDA approval
of bosutinib (Bosulif). Like imatinib, dasatinib, and nilotinib,
bosutinib blocks the activity of BRC-ABL but fails to block the
T315I BCR-ABL mutant. Its use as a treatment for CML was
approved by the FDA after it was shown to have anti-leukemic
activity in patients with CML resistant to one or more of
imatinib, dasatinib, and nilotinib (144). The second was the
October 2012 FDA approval of omacetaxine mepesuccinate
(Synribo). Understanding how omacetaxine mepesuccinate
works is an area of active investigation; currently, it seems that
