Introduction:
Cancer is a heterogeneous and highly complex disease that annually
claims the lives of millions of people, making it one of the leading
causes of death worldwide [1]. The number of deaths caused by cancer
is growing increasingly and predictions indicate that it will continue
to do so. Estimates show that in 2018, 9.6 million cancer-related deaths
occurred [2]. However, by 2030, it is projected that around 30
million people may die annually from cancer [2]. That is why cancer
is a very serious challenge for public health worldwide, and it becomes
increasingly widespread and severe every year. Although there are
innovative and diverse methods for cancer treatment, four treatment
methods are conventional and usually employed to combat cancer,
including surgery, radiation therapy, immunotherapy, and chemotherapy.
Chemotherapy, however, faces many challenges such as non-specific
targeting of cancer cells, treatment resistance, and cancer recurrence
even after successful treatment. The use of targeted small-molecule
drugs is one of the ways to improve the outcome of chemotherapy. Because
of their low molecular weight (<1000 Da) and small size, they
can bind to various targets outside and inside the cell [3]. Since
2001, when the first small molecule tyrosine kinase inhibitor (TKI)
drug, imatinib, by the US Food and Drug Administration (FDA), was
approved for clinical use, more than 80 small molecule drugs for cancer
treatment have been approved by the US FDA and the National Medical
Products Administration (NMPA) of China [4]. However, the
therapeutic results of targeted small molecules are limited. Cancer
cells use a variety of factors and strategies to fight and resist
chemotherapy. For this reason, to improve the results of treatments
based on small molecules as adjunctive therapy to overcome the
challenges of chemotherapy, knowledge and deep understanding of
chemotherapy resistance mechanisms and then determining the most
effective and main factors as targets for small molecules is very
crucial and important. In this study, most of these factors and
mechanisms are comprehensively examined in four titles including tumor
microenvironment, immunomodulation, DNA repair mechanisms, and cancer
stem cells. It is crucial and essential for drug designers and
scientists to extensively investigate these mechanisms for the proper
and effective design of targeted small molecule drugs as adjunctive
chemotherapy treatments.